NEW APPROACHES IN UNDERSTANDING DRUG METABOLISM

Limitations in technology, such as DNA sequencing and appropriate model systems, have made it difficult to understand the genetic and non-genetic factors that influence the liver's role in metabolizing drugs. New approaches are required to overcome these limitations. In this Dissertation, we evaluate 3 such new approaches. Our first new approach relates to the field of pharmacogenetics: using genetics to predict how a patient will respond to medication based on their genetic code. We looked for polymorphisms in a novel target gene, Cytochrome P450 Oxidoreductase (POR). Our results show a mutation in P450 reductase (L577P) that associates with decreased metabolism for 8 of 10 major drug metabolizing enzymes. However, even though we found a statistical association between POR polymorphism and drug metabolism, a wide range of variation in POR activity was still observed among the samples with the L577/ P577 genotype, making predicting POR activity solely on the basis of L577P genotype difficult. POR represents only a single gene amongst the tens of thousands present in the human genome. To investigate the relationship between how genes and their products interact, a systems approach is necessary. Therefore, in our second new approach, we will characterize the transcriptome of our model system, the HepaRG cell line. We found that HepaRG cells globally transcribe genes at the levels more similar to human primary hepatocytes and human liver than HepG2 cells, particularly in genes encoding drug processing proteins. Finally, I describe the third new approach: the use of next-generation DNA sequencing to understand hepatic drug response. This section contains two parts. First, we introduce methods that significantly decrease the false discovery rate of genotyping from RNA-Seq data. With these high fidelity SNPs, we were able to perform a genome-wide pharmacogenomic analysis on HepaRG cells. Second, we introduce a new program, called PRUNE, to more accurately quantify gene expression, and compare its performance to that of established programs

Education Reform: Oklahoma Superintendents' Perceptions of House Bill 1017 from 1990-1995

Educational Administratio

Seeding Techniques for Alfalfa to Improve Subirrigated Meadows

Improving quality and quantity of forage harvested from poor condition, subirrigated hay meadows in the Nebraska Sand Hills is critical to the winter forage reserve of livestock producers. Alfalfa (Medicago sativa L.) is the most commonly used legume for meadow improvement. Broadcast seeding (11.2 kg/ha) was compared to sod seeding (11.2 kg/ha) as a method to introduce alfalfa into an alkaline subirrigated meadow (Fluvaquentic Haplustolls). Before seeding, the study area received 78.5 kg/ha phosphorous. Paraquat (0.29 kg/ha) was applied to one-half of the area to suppress plant competition and provide qualitative information on treatment consistency across a range of sod competition. Lo-till sod seeding was accomplished with a power tillage seeder. Seedling density was determined in spring the following year. Broadcast alfalfa had a greater seedling density than sod-seeded alfalfa (38.4 and 19.1 plants/m2, respectively, p=.09). Apparently, paraquat had no effect on seedling establishment and tended to reduce total yield. Yields the year of seeding, using a two harvest scheme, were greater for broadcast compared to sod-seeded alfalfa (p=.02). However, there was no significant difference between yields of broadcast alfalfa and control

Microarray analysis of the in vivo sequence preferences of a minor groove binding drug

<p>Abstract</p> <p>Background</p> <p>Minor groove binding drugs (MGBDs) interact with DNA in a sequence-specific manner and can cause changes in gene expression at the level of transcription. They serve as valuable models for protein interactions with DNA and form an important class of antitumor, antiviral, antitrypanosomal and antibacterial drugs. There is a need to extend knowledge of the sequence requirements for MGBDs from <it>in vitro </it>DNA binding studies to living cells.</p> <p>Results</p> <p>Here we describe the use of microarray analysis to discover yeast genes that are affected by treatment with the MGBD berenil, thereby allowing the investigation of its sequence requirements for binding <it>in vivo</it>. A novel approach to sequence analysis allowed us to address hypotheses about genes that were directly or indirectly affected by drug binding. The results show that the sequence features of A/T richness and heteropolymeric character discovered by <it>in vitro </it>berenil binding studies are found upstream of genes hypothesized to be directly affected by berenil but not upstream of those hypothesized to be indirectly affected or those shown to be unaffected.</p> <p>Conclusion</p> <p>The data support the conclusion that effects of berenil on gene expression in yeast cells can be explained by sequence patterns discovered by <it>in vitro </it>binding experiments. The results shed light on the sequence and structural rules by which berenil binds to DNA and affects the transcriptional regulation of genes and contribute generally to the development of MGBDs as tools for basic and applied research.</p

Organizational preparedness for the use of large language models in pathology informatics

In this paper, we consider the current and potential role of the latest generation of Large Language Models (LLMs) in medical informatics, particularly within the realms of clinical and anatomic pathology. We aim to provide a thorough understanding of the considerations that arise when employing LLMs in healthcare settings, such as determining appropriate use cases and evaluating the advantages and limitations of these models. Furthermore, this paper will consider the infrastructural and organizational requirements necessary for the successful implementation and utilization of LLMs in healthcare environments. We will discuss the importance of addressing education, security, bias, and privacy concerns associated with LLMs in clinical informatics, as well as the need for a robust framework to overcome regulatory, compliance, and legal challenges

Dynamic Patterns of Histone Methylation Are Associated with Ontogenic Expression of the Cyp3a Genes during Mouse Liver Maturation

ABSTRACT Human cytochrome P450 3A (CYP3A) members are major drugmetabolizing enzymes in the liver. Two genes, CYP3A4 and CYP3A7, exhibit a developmental switch in gene expression during liver maturation. CYP3A4 is mainly expressed in adults, whereas CYP3A7 is dominantly expressed during the fetal and neonatal stages. Their ontogenic expression results in developmentally related changes in the capacity to metabolize endogenous and exogenous compounds

Galaxy Zoo and SPARCFIRE: constraints on spiral arm formation mechanisms from spiral arm number and pitch angles

In this paper, we study the morphological properties of spiral galaxies, including measurements of spiral arm number and pitch angle. Using Galaxy Zoo 2, a stellar mass-complete sample of 6222 SDSS spiral galaxies is selected. We use the machine vision algorithm sparcfire to identify spiral arm features and measure their associated geometries. A support vector machine classifier is employed to identify reliable spiral features, with which we are able to estimate pitch angles for half of our sample. We use these machine measurements to calibrate visual estimates of arm tightness, and hence estimate pitch angles for our entire sample. The properties of spiral arms are compared with respect to various galaxy properties. The star formation properties of galaxies vary significantly with arm number, but not pitch angle. We find that galaxies hosting strong bars have spiral arms substantially (4°-6°) looser than unbarred galaxies. Accounting for this, spiral arms associated with many-armed structures are looser (by 2°) than those in two-armed galaxies. In contrast to this average trend, galaxies with greater bulge-to-total stellar mass ratios display both fewer and looser spiral arms. This effect is primarily driven by the galaxy disc, such that galaxies with more massive discs contain more spiral arms with tighter pitch angles. This implies that galaxy central mass concentration is not the dominant cause of pitch angle and arm number variations between galaxies, which in turn suggests that not all spiral arms are governed by classical density waves or modal theories

Galaxy Zoo: secular evolution of barred galaxies from structural decomposition of multiband images

We present the results of two-component (disc+bar) and three-component (disc+bar+bulge) multiwavelength 2D photometric decompositions of barred galaxies in five Sloan Digital Sky Survey (SDSS) bands (ugriz). This sample of ∼3500 nearby (z<0.06) galaxies with strong bars selected from the Galaxy Zoo citizen science project is the largest sample of barred galaxies to be studied using photometric decompositions that include a bar component. With detailed structural analysis, we obtain physical quantities such as the bar- and bulge-to-total luminosity ratios, effective radii, Sersic indices and colours of the individual components. We observe a clear difference in the colours of the components, the discs being bluer than the bars and bulges. An overwhelming fraction of bulge components have Sersic indices consistent with being pseudo-bulges. By comparing the barred galaxies with a mass-matched and volume-limited sample of unbarred galaxies, we examine the connection between the presence of a large-scale galactic bar and the properties of discs and bulges. We find that the discs of unbarred galaxies are significantly bluer compared to the discs of barred galaxies, while there is no significant difference in the colours of the bulges. We find possible evidence of secular evolution via bars that leads to the build-up of pseudo-bulges and to the quenching of star formation in the discs. We identify a subsample of unbarred galaxies with an inner lens/oval and find that their properties are similar to barred galaxies, consistent with an evolutionary scenario in which bars dissolve into lenses. This scenario deserves further investigation through both theoretical and observational work

Galaxy Zoo: finding offset discs and bars in SDSS galaxies

We use multiwavelength Sloan Digital Sky Survey (SDSS) images and Galaxy Zoo morphologies to identify a sample of ∼270 late-type galaxies with an off-centre bar. We measure offsets in the range 0.2–2.5 kpc between the photometric centres of the stellar disc and stellar bar. The measured offsets correlate with global asymmetries of the galaxies, with those with largest offsets showing higher lopsidedness. These findings are in good agreement with predictions from simulations of dwarf–dwarf tidal interactions producing off-centre bars. We find that the majority of galaxies with off-centre bars are of Magellanic type, with a median mass of 109.6 M⊙, and 91 per cent of them having M⋆ < 3 × 1010 M⊙, the characteristic mass at which galaxies start having higher central concentrations attributed to the presence of bulges. We conduct a search for companions to test the hypothesis of tidal interactions, but find that a similar fraction of galaxies with offset bars have companions within 100 kpc as galaxies with centred bars. Although this may be due to the incompleteness of the SDSS spectroscopic survey at the faint end, alternative scenarios that give rise to offset bars such as interactions with dark companions or the effect of lopsided halo potentials should be considered. Future observations are needed to confirm possible low-mass companion candidates and to determine the shape of the dark matter halo, in order to find the explanation for the off-centre bars in these galaxies

Gender Differences in Russian Colour Naming

In the present study we explored Russian colour naming in a web-based psycholinguistic experiment (http://www.colournaming.com). Colour singletons representing the Munsell Color Solid (N=600 in total) were presented on a computer monitor and named using an unconstrained colour-naming method. Respondents were Russian speakers (N=713). For gender-split equal-size samples (NF=333, NM=333) we estimated and compared (i) location of centroids of 12 Russian basic colour terms (BCTs); (ii) the number of words in colour descriptors; (iii) occurrences of BCTs most frequent non-BCTs. We found a close correspondence between females’ and males’ BCT centroids. Among individual BCTs, the highest inter-gender agreement was for seryj ‘grey’ and goluboj ‘light blue’, while the lowest was for sinij ‘dark blue’ and krasnyj ‘red’. Females revealed a significantly richer repertory of distinct colour descriptors, with great variety of monolexemic non-BCTs and “fancy” colour names; in comparison, males offered relatively more BCTs or their compounds. Along with these measures, we gauged denotata of most frequent CTs, reflected by linguistic segmentation of colour space, by employing a synthetic observer trained by gender-specific responses. This psycholinguistic representation revealed females’ more refined linguistic segmentation, compared to males, with higher linguistic density predominantly along the redgreen axis of colour space