Letter representations in the mind and brain

Letter identification imposes numerous challenges on the brain's visual system. Identification processes must be flexible enough to recognize that ear and Ear refer to the same word while being precise enough to recognize that lend me your ear and lend me your car have different meanings. At the core of this dissertation is the assumption that the flexibility and precision which enables us to effortlessly recognize letters is based on our mental representations of letters. The experiments presented focus on two types of letter representations: font-invariant allographs and amodal abstract letter identities (ALIs). First, a set of behavioral experiments demonstrated that stored, font-invariant letter shape (allograph) representations influenced the visually similarity judgments participants made to pairs of letters presented in an atypical font. Following this result, an fMRI experiment was performed in which the neural response to visually presented single letter stimuli was analyzed using Representational Similarity Analysis (RSA). This analysis yielded evidence for allograph representations encoded within the left middle occipital gyrus and left fusiform gyrus. Finally, MVPA RSA analyses were employed to compare the patterns of neural responses to visually presented letter shapes and aurally presented letter names. This experiment revealed a region in the left fusiform gyrus that represented amodal ALIs (e.g., a, A, and /eI/ access the same amodal ALI). The research in this dissertation furthers our understanding of the representations that mediate letter identification and the results touch upon fundamental issues about the nature of information processing in cognitive science

Shifts in targeting of class switch recombination sites in mice that lack mu switch region tandem repeats or Msh2

The mechanisms that target class switch recombination (CSR) to antibody gene switch (S) regions are unknown. Analyses of switch site locations in wild-type mice and in mice that lack the Smu tandem repeats show shifts indicating that a 4-5-kb DNA domain (bounded upstream by the Imu promoter) is accessible for switching independent of Smu sequences. This CSR-accessible domain is reminiscent of the promoter-defined domains that target somatic hypermutation. Within the 4-5-kb CSR domain, the targeting of S site locations also depends on the Msh2 mismatch repair protein because Msh2-deficient mice show an increased focus of sites to the Smu tandem repeat region. We propose that Msh2 affects S site location because sequences with few activation-induced cytidine deaminase targets generate mostly switch DNA cleavages that require Msh2-directed processing to allow CSR joining

Shifts in targeting of class switch recombination sites in mice that lack μ switch region tandem repeats or Msh2

The mechanisms that target class switch recombination (CSR) to antibody gene switch (S) regions are unknown. Analyses of switch site locations in wild-type mice and in mice that lack the Sμ tandem repeats show shifts indicating that a 4–5-kb DNA domain (bounded upstream by the Iμ promoter) is accessible for switching independent of Sμ sequences. This CSR-accessible domain is reminiscent of the promoter-defined domains that target somatic hypermutation. Within the 4–5-kb CSR domain, the targeting of S site locations also depends on the Msh2 mismatch repair protein because Msh2-deficient mice show an increased focus of sites to the Sμ tandem repeat region. We propose that Msh2 affects S site location because sequences with few activation-induced cytidine deaminase targets generate mostly switch DNA cleavages that require Msh2-directed processing to allow CSR joining

Variation in Organophosphate Pesticide Metabolites in Urine of Children Living in Agricultural Communities

Children of migrant farmworkers are at increased risk of exposure to organophosphate pesticides because of “carry-home” transport processes and residential location. Although this at-risk status is generally recognized, few available reports describe the extent of this exposure among agricultural communities. We quantified dialkyl phosphate (DAP) levels in serial samples of urine from 176 children, 2–6 years of age, in three Oregon communities hosting differing agricultural industries: pears, cherries, and fruit berries. Up to three spot samples of urine were collected from children at the beginning, mid-point, and end of their parents’ work seasons. The median levels of dimethylthiophosphate (DMTP), the most commonly detected metabolite, was significantly higher in urine samples from children in each of the three agricultural communities (17.5, 19.0, and 41.0 ng/mL) relative to a reference group of children who lived in an urban community and whose parents did not work in agriculture (6.5 ng/mL; Kruskal-Wallis, p < 0.001). After controlling for age, sex, and weight, the median level of DMTP in children in the pear community was 1.92 times higher than the level in children of the berry community [95% confidence interval (CI), 1.14–3.23] and 1.75 times higher than the level in children of the cherry community (95% CI, 0.95–3.23). We observed increasing levels of DMTP across the work season only within the berry community. Levels decreased in the cherry community and remained constant in the pear community. Substantial temporal variation within the children followed demonstrates the need for multiple urine samples to most accurately characterize longer term and/or cumulative exposure. The observed variability in urinary DAP levels, between communities and over time, could be attributed to the types and amounts of organophosphate pesticides used, the timing of applications and degradation of residues in the environment, work operations and hygiene practices, the proximity of housing to orchards and fields, or the movement of these working families. Additional studies of variation in pesticide exposure across agricultural regions are needed

Organophosphate Pesticide Exposure and Neurobehavioral Performance in Agricultural and Nonagricultural Hispanic Workers

Our understanding of the health risks of farmworkers exposed to pesticides in their work and home environments is rapidly increasing, although studies designed to examine the possible neurobehavioral effects of low-level chronic pesticide exposure are limited. We measured dialkyl phosphate urinary metabolite levels, collected environmental dust samples from a subset of homes, obtained information on work practices, and conducted neurobehavioral tests on a sample of farmworkers in Oregon. Significant correlations between urinary methyl metabolite levels and total methyl organophosphate (azinphos-methyl, phosmet, malathion) house dust levels were observed. We found the neurobehavioral performance of Hispanic immigrant farmworkers to be lower than that observed in a nonagricultural Hispanic immigrant population, and within the sample of agricultural workers there was a positive correlation between urinary organophosphate metabolite levels and poorer performance on some neurobehavioral tests. These findings add to an increasing body of evidence of the association between low levels of pesticide exposure and deficits in neurobehavioral performance

Effects of AgRP Inhibition on Energy Balance and Metabolism in Rodent Models

Activation of brain melanocortin-4 receptors (MC4-R) by α-melanocyte-stimulating hormone (MSH) or inhibition by agouti-related protein (AgRP) regulates food intake and energy expenditure and can modulate neuroendocrine responses to changes in energy balance. To examine the effects of AgRP inhibition on energy balance, a small molecule, non-peptide compound, TTP2515, developed by TransTech Pharma, Inc., was studied in vitro and in rodent models in vivo. TTP2515 prevented AgRP from antagonizing α-MSH-induced increases in cAMP in HEK 293 cells overexpressing the human MC4-R. When administered to rats by oral gavage TTP2515 blocked icv AgRP-induced increases in food intake, weight gain and adiposity and suppression of T4 levels. In both diet-induced obese (DIO) and leptin-deficient mice, TTP2515 decreased food intake, weight gain, adiposity and respiratory quotient. TTP2515 potently suppressed food intake and weight gain in lean mice immediately after initiation of a high fat diet (HFD) but had no effect on these parameters in lean chow-fed mice. However, when tested in AgRP KO mice, TTP2515 also suppressed food intake and weight gain during HFD feeding. In several studies TTP2515 increased T4 but not T3 levels, however this was also observed in AgRP KO mice. TTP2515 also attenuated refeeding and weight gain after fasting, an effect not evident in AgRP KO mice when administered at moderate doses. This study shows that TTP2515 exerts many effects consistent with AgRP inhibition however experiments in AgRP KO mice indicate some off-target effects of this drug. TTP2515 was particularly effective during fasting and in mice with leptin deficiency, conditions in which AgRP is elevated, as well as during acute and chronic HFD feeding. Thus the usefulness of this drug in treating obesity deserves further exploration, to define the AgRP dependent and independent mechanisms by which TTP2515 exerts its effects on energy balance