Creation of Curriculum Reality: Metaphors in Education

Curriculum and Instructio

Problem Solving Abilities of Young Children as a Function of Three Sensory Conditions

This study analyzes the performances of 330 children representing kindergarten, first grade, second grade, third grade, and fourth grade on two class-inclusion problem-solving tasks each presented in one of three randomly assigned sensory conditions as follows: auditory, auditory-visual, or auditory-visual-kinesthetic. The purpose of this investigation is to observe the effects of increasing amounts of sensory stimuli on the problem-solving abilities of young children.Applied Behavioral Studie

Advancements in the understanding of staphylococcal mastitis through the use of molecular tools

The objectives of this work were: 1) to complete a whole genome sequence of a Staphylococcus chromogenes isolate that is known to persist in the mammary gland of a cow, 2) to define a genetic target that could easily and reliably be used to differentiate Staphylococcus agnetis and Staphylococcus hyicus and to use this new assay along with pulsed-field gel electrophoresis (PFGE) strain typing to characterize a collection of non-Staphylococcus aureus coagulase positive staphylococci, 3) to determine if the recently described S. aureus Genotype B was present among previously characterized isolates from cases of bovine intramammary infection in the USA and to compare PFGE to the combination of ribosomal spacer PCR (RS-PCR) and virulence gene identification for strain typing of S. aureus, 4) to further the understanding of the association between body site colonization and intramammary infection before and after calving in heifers using molecular methods of speciation and strain typing, and 5) to describe the prevalence and distribution of Staphylococcus species on the teat and inguinal skin of dairy heifers throughout the heifer lifecycle using molecular speciation methods. A draft genome sequence of S. chromogenes MU 970, a strain that was isolated from the right rear quarter of a Holstein cow for 16 consecutive months, was completed. Whole genome sequences for S. chromogenes, S. hyicus, and S. agnetis were then used to construct a multiplex PCR used to differentiate S. hyicus, S. agnetis, and S. aureus. The multiplex PCR was then used to characterize a collection of isolates and found that S. agnetis was much more prevalent than S. hyicus. Furthermore, S. agnetis can cause persistent infections and can potentially be contagious. Next, RS-PCR plus toxin gene identification was explored as a possible strain typing method, however it was found to be less discriminatory than PFGE. Hence, PFGE was used as the strain typing method for the remainder of the dissertation research. The final two studies were conducted to characterize body site colonization with staphylococcal species and to explore the relationship of prepartum body site colonization to intramammary infections, both pre- and post-calving. MALDI-TOF was explored as a speciation method in these studies and was found to be accurate, rapid, and inexpensive. Overall, S. chromogenes was the most common species identified in prepartum mammary secretions and post-calving milk samples. Through PFGE strain typing, it was determined that many different strains of each species can be found on one heifer. Finally, it was determined that colonization of the inguinal region and teat skin was associated with age for S. agnetis, S. chromogenes, Staphylococcus devriesei, Staphylococcus equorum, Staphylococus haemolyticus, Staphylococcus lentus, Staphylococcus sciuri, Staphylococcus vitulinus, and Staphylococcus xylosus. Overall, these studies demonstrate that the staphylococcal species and subspecies associated with IMI are extremely abundant and diverse on dairy farms.Includes biblographical reference

A Role for Thymic Stromal Lymphopoietin in CD4+ T Cell Development

Thymic stromal lymphopoietin (TSLP) signals via a receptor comprising the interleukin (IL)-7 receptor α chain and a distinctive subunit, TSLP receptor (TSLPR), which is most related to the common cytokine receptor γ chain, γc. We have generated TSLPR knockout (KO) mice and found that although these mice had normal lymphocyte numbers, γc/TSLPR double KO mice had a greater lymphoid defect than γc KO mice. This indicates that TSLP contributes to lymphoid development and accounts for some of the residual lymphoid development in γc KO mice and presumably in patients with X-linked severe combined immunodeficiency. Injection of TSLP into γc KO mice induced the expansion of T and B cells. Moreover, sublethally irradiated TSLPR KO mice showed weaker recovery of lymphocyte populations than wild-type (WT) littermates, even when neutralizing anti–IL-7 antibodies were injected. Interestingly, TSLP preferentially stimulated the proliferation and survival of CD4+ single positive thymocytes and peripheral T cells in vitro. Additionally, CD4+ T cells from TSLPR KO mice expanded less efficiently than WT CD4+ T cells in irradiated hosts, and TSLP preferentially expanded CD4+ T cells both in vitro and in vivo. Thus, as compared with other known cytokines, TSLP is distinctive in exhibiting a lineage preference for the expansion and survival of CD4+ T cells

Pyrrolo[2,3D]Pyrimidine Compounds

Described herein is pyrrolo{2,3-d}pyrimidine compounds, their use as Janus Kinase (JAK) inhibitors, pharmaceutical compositions containing this compounds, and methods for the preparation of these compounds

Cadmium levels in a North Carolina cohort: Identifying risk factors for elevated levels during pregnancy

The objectives of this study were to examine cadmium (Cd) levels and relationships to demographics in an observational, prospective pregnancy cohort study in Durham County, North Carolina. Multivariable models were used to compare blood Cd levels across demographic characteristics. The relative risk of having a blood Cd level that exceeds the US national median (0.32 μg/l) was estimated. Overall, >60% of the women had an elevated (>0.32 μg/l) blood Cd level. Controlling for confounding variables, smoking was associated with 21% (95% CI: 15–28%) increased risk for an elevated blood Cd level. High Cd levels were also observed in non-smokers and motivated smoking status-stratified models. Race, age, education, relationship status, insurance status and cotinine level were not associated with risk of elevated Cd levels among smokers; however, older age and higher cotinine levels were associated with elevated Cd levels among non-smokers. Taken together, more than half of pregnant women in this cohort had elevated blood Cd levels. Additionally, among non-smokers, 53% of the women had elevated levels of Cd, highlighting other potential sources of exposure. This study expands on the limited data describing Cd levels in pregnant populations and highlights the importance of understanding Cd exposures among non-smokers. Given the latent health risks of both smoking and Cd exposure, this study further highlights the need to biomonitor for exposure to toxic metals during pregnancy among all women of child-bearing age

Population Genetic Study of the Brain-Derived Neurotrophic Factor (BDNF) Gene

Genetic variants in the brain-derived neurotrophic factor (BDNF) gene, predominantly the functional Val66Met polymorphism, have been associated with risk of bipolar disorder and other psychiatric disorders. However, not all studies support these findings, and overall the evidence for the association of BDNF with disease risk is weak. As differences in population genetic structure between patient samples could cause discrepant or spurious association results, we investigated this possibility by carrying out population genetic analyses of the BDNF genomic region. Substantial variation was detected in BDNF coding region single-nucleotide polymorphism (SNP) allele and haplotype frequencies between 58 global populations, with the derived Met allele of Val66Met ranging in frequency from 0 to 72% across populations. FST analyses to assess diversity in the HapMap populations determined that the Val66Met FST value was at the 99.8th percentile among all SNPs in the genome. As the BDNF population genetic differences may be due to local selection, we performed the long-range haplotype test for selection using 68 SNPs spanning the BDNF genomic region in 12 European-derived pedigrees. Evidence for positive selection was found for a high-frequency Val-carrying haplotype, with a relative extended haplotype homozygosity value above the 99th percentile compared with HapMap data $(P=4.6 \times 10^{−4})$. In conclusion, we observed considerable BDNF allele and haplotype diversity among global populations and evidence for positive selection at the BDNF locus. These phenomena can have a profound impact on the detection of disease susceptibility genes and must be considered in gene association studies of BDNF.Organismic and Evolutionary BiologyOther Research Uni

Maternal Cadmium Levels during Pregnancy Associated with Lower Birth Weight in Infants in a North Carolina Cohort

Cadmium (Cd) is a ubiquitous environmental contaminant, a known carcinogen, and understudied as a developmental toxicant. In the present study, we examined the relationships between Cd levels during pregnancy and infant birth outcomes in a prospective pregnancy cohort in Durham, North Carolina. The study participants (n = 1027) had a mean Cd level of 0.46 µg/L with a range of <0.08 to 2.52 µg/L. Multivariable models were used to establish relationships between blood Cd tertiles and fetal growth parameters, namely birth weight, low birth weight, birth weight percentile by gestational age, small for gestational age, pre-term birth, length, and head circumference. In multivariable models, high maternal blood Cd levels (≥0.50 µg/L) during pregnancy were inversely associated with birth weight percentile by gestational age (p = 0.007) and associated with increased odds of infants being born small for gestational age (p<0.001). These observed effects were independent of cotinine-defined smoking status. The results from this study provide further evidence of health risks associated with early life exposure to Cd among a large pregnancy cohort

ERK and mTORC1 Inhibitors Enhance the Anti-Cancer Capacity of the Octpep-1 Venom-Derived Peptide in Melanoma BRAF(V600E) Mutations

Melanoma is the main cause of skin cancer deaths, with special emphasis in those cases carrying BRAF mutations that trigger the mitogen-activated protein kinases (MAPK) signaling and unrestrained cell proliferation in the absence of mitogens. Current therapies targeting MAPK are hindered by drug resistance and relapse that rely on metabolic rewiring and Akt activation. To identify new drug candidates against melanoma, we investigated the molecular mechanism of action of the Octopus Kaurna-derived peptide, Octpep-1, in human BRAF(V600E) melanoma cells using proteomics and RNAseq coupled with metabolic analysis. Fluorescence microscopy verified that Octpep-1 tagged with fluorescein enters MM96L and NFF cells and distributes preferentially in the perinuclear area of MM96L cells. Proteomics and RNAseq revealed that Octpep-1 targets PI3K/AKT/mTOR signaling in MM96L cells. In addition, Octpep-1 combined with rapamycin (mTORC1 inhibitor) or LY3214996 (ERK1/2 inhibitor) augmented the cytotoxicity against BRAF(V600E) melanoma cells in comparison with the inhibitors or Octpep-1 alone. Octpep-1-treated MM96L cells displayed reduced glycolysis and mitochondrial respiration when combined with LY3214996. Altogether these data support Octpep-1 as an optimal candidate in combination therapies for melanoma BRAF(V600E) mutations

Sequence-based prediction for vaccine strain selection and identification of antigenic variability in foot-and-mouth disease virus

Identifying when past exposure to an infectious disease will protect against newly emerging strains is central to understanding the spread and the severity of epidemics, but the prediction of viral cross-protection remains an important unsolved problem. For foot-and-mouth disease virus (FMDV) research in particular, improved methods for predicting this cross-protection are critical for predicting the severity of outbreaks within endemic settings where multiple serotypes and subtypes commonly co-circulate, as well as for deciding whether appropriate vaccine(s) exist and how much they could mitigate the effects of any outbreak. To identify antigenic relationships and their predictors, we used linear mixed effects models to account for variation in pairwise cross-neutralization titres using only viral sequences and structural data. We identified those substitutions in surface-exposed structural proteins that are correlates of loss of cross-reactivity. These allowed prediction of both the best vaccine match for any single virus and the breadth of coverage of new vaccine candidates from their capsid sequences as effectively as or better than serology. Sub-sequences chosen by the model-building process all contained sites that are known epitopes on other serotypes. Furthermore, for the SAT1 serotype, for which epitopes have never previously been identified, we provide strong evidence - by controlling for phylogenetic structure - for the presence of three epitopes across a panel of viruses and quantify the relative significance of some individual residues in determining cross-neutralization. Identifying and quantifying the importance of sites that predict viral strain cross-reactivity not just for single viruses but across entire serotypes can help in the design of vaccines with better targeting and broader coverage. These techniques can be generalized to any infectious agents where cross-reactivity assays have been carried out. As the parameterization uses pre-existing datasets, this approach quickly and cheaply increases both our understanding of antigenic relationships and our power to control disease