The new compact disc from the Department of Veterans Affairs, Tonal and Speech Materials for Auditory Perceptual Assessment, Disc 2.0 (1998), contains two lists of randomly interleaved 1-, 2-, and 3-pair dichotic digits. Two experiments are reported, in which the effects of low-pass filtering and inter-digit interval on dichotic digit recognition were investigated in adult listeners with normal hearing and with mild-to-moderate cochlear hearing loss. Results demonstrated that in the filtered condition, as the low-pass cutoff was increased, there was an increase in recognition performance for 1-, 2-, and 3-pair dichotic digits. When compared to normative data for the materials, findings indicate that the interleaved 1-, 2-, and 3-pair dichotic digit materials were essentially resistant to the effects of hearing loss. There was no significant change in recognition performance as a function of inter-digit interval. The studied 625-ms range of inter-digit intervals studied produced consistent recognition performance with both groups of listeners.

Continuous integration and delivery (CI/CD) frameworks are a core element of DevOps-based software development. A PHP-based case study assessed the suitability of five such frameworks - -JFrog Arti-factory, Bitbucket Pipelines, Jenkins, Azure DevOps, and TeamCity - -for instructional use. The five were found to be roughly equivalent in terms of their usability for simple configurations. The effort needed to implement CI/CD substantially increased for more realistic production scenarios, like deployments to cloud and load-balanced platforms. These results suggest a need to limit CI/CD-based academic projects to simple infrastructure and technology stacks: e.g., a web application on a single instance web server.

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Linker histones (H1) are the basic proteins in higher eukaryotes that are responsible for the final condensation of chromatin. H1 also plays an important role in regulating gene expression. H1 has been described as a transcriptional repressor as it limits the access of transcriptional factors to DNA. Linker histone binds to DNA that enters or exits the nucleosome. Several crystal structures have been published for the nucleosome (histone core/DNA complex), and the interactions of the core histone proteins with DNA are well understood. In contrast the location of the linker histone and its interactions with ds-DNA are poorly understood. In this study we have used isothermal titration calorimetry (ITC), differential scanning calorimetry (DSC), and CD spectropolarimetry to determine the thermodynamic signatures and structural changes that accompany H1 binding to ds-DNA. The thermodynamic parameters for the binding of intact linker histones (H1.1, H1.4, and H10) to highly polymerized calf-thymus DNA and to short double stranded DNA oligomers have been determined. We have also determined the thermodynamics for binding of H10 C-terminal tail (H10-C) and globular domain (H10-G) to calf-thymus DNA. The real surprise in the energetics is that the enthalpy change for formation of the H1/DNA complex is very unfavorable and that H1/DNA complex formation is driven by very large positive changes in entropy. The binding site sizes for H1.1, H1.4, and H10 were determined to be 36bp, 32bp, and 36bp respectively. CD results indicate that CT-DNA is restructured upon complexation with either the full length H1 protein (H10) or its C-terminal domain (H10-C). In contrast, the structure of H10 is largely unchanged in the DNA complex. Temperature dependence of enthalpy change, osmotic stress and ionic strength dependence of Ka were tested using ITC. These results indicate that the entropy driven H1/DNA complexes are a result primarily from the expulsion of bound water molecules from the binding interface. This study provides new insights into the binding of linker Histone H1 to DNA. A better understanding of the functional properties of H1 and its interactions with DNA could provide new insights in understanding the role H1 in DNA condensation and transcriptional regulation.

The oncogene c-MYC has guanine-rich and complementary cytosine-rich sequences in its P1 promoter region. The P1 promoter is responsible for over 90% of the c-MYC expression. Downregulation of c-MYC expression represents a novel therapeutic approach to more than 50% of all cancers. A stable i-motif formed by the c-MYC C-rich sequence would be an attractive target for cancer treatment. We have previously shown that c-MYC promoter sequences can form stable i-motifs in acidic solution (pH 4.5-5.5). The question is whether c-MYC promoter sequence i-motif will be stable at physiological pH. In this work, we have investigated the stability of mutant c-MYC i-motif in solutions having pH values from 4 to 7 and containing co-solutes or molecular crowding agents. The crowded nuclear environment was modeled by the addition of polyethylene glycol (PEG, having molecular weights from 200 to 12000 g/mol) at concentrations of 10% to 40% w/w. Circular dichroism spectroscopy (CD) and differential scanning calorimetry (DSC) were used to establish the presence and stability of c-MYC i-motifs in buffer solutions having pH values of 4 to 7. The results of these studies are: 1) the addition of up to 20% w/w glycerol does not increase i-motif stability, 2) the addition of 30% PEG results in an increase in i-motif stability to pH values as high as 6.7, 3) i-motif stability is increased with increased PEG concentration and increased PEG molecular weight, and 4) the effects of PEG size and concentration are not linear, with larger PEGs forming DNA/PEG complexes, which destabilize the i-motif. In summary, we have shown that the c-MYC i-motif can exist as a stable structure at pH as high as 6.7 in a crowded environment. Molecular crowding, largely an excluded volume effect, drives the formation of the more compact i-motif, even at higher pH values where the cytosine imino-nitrogen is deprotonated and neutral C-C pairs can form only two H-bonds. Based on this research, it seems possible that a stable c-MYC promoter sequence i-motif could form at physiological pH and would be a reasonable drug target for new cancer therapies.

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<p>  </p> <p>Mushrooms, unique edible fungi, contain several essential nutrients and bioactive compounds including L-ergothioneine, beta-glucans, and lovastatin, which may improve cardiometabolic health through their anti-inflammatory, cholesterol-lowering, and antioxidant properties, respectively. Despite a long history of consumption, the chemical composition and health benefits of mushrooms are not well documented. Research included in this dissertation aims to document the unique properties of dietary mushrooms and their effects on cardiometabolic disease risk factors in middle-aged and older adults. Thematically, this research describes mushrooms from a nutrient, food, and dietary pattern perspective. Using untargeted liquid chromatography mass spectrometry (LC/MS)-based metabolomics, we detected over 10,000 compounds in seven mushroom varieties, each sourced from two farms (3 replicates/farm). Over 1,300 compounds were detected in all seven mushroom varieties, supporting some level of similarity. In contrast, each variety had tens-to-hundreds of unique-to-mushroom variety compounds, ranging from 29 for crimini to 854 for lion’s mane. Amino acid analysis revealed <em>Agaricus bisporus</em> varieties (white button, crimini, portabella) had similar amino acid profiles, including detection of all nine essential amino acids, while other varieties (lion’s mane, maitake, oyster, shiitake) had less methionine and tryptophan. Collectively, these findings highlight not all mushrooms are chemically comparable. From a food/dietary pattern perspective, experimental evidence from a systematically searched literature review indicate greater mushroom consumption reduces blood triglycerides and hs-CRP. Evidence from observational research indicate mixed, albeit neutral to positive, associations between mushroom consumption and most cardiometabolic health outcomes. Results from our randomized controlled trial indicate adoption of a healthy dietary pattern with mushrooms improves fasting blood glucose and dense LDL III. Adoption of a healthy dietary pattern, independent of mushroom consumption, improves total cholesterol and non-LDL cholesterol. Results from the research presented in this dissertation confirm mushrooms are nutritionally unique and may improve several risk factors for cardiometabolic diseases with regular consumption.</p>

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