Molecular Genetics of MS4A6A and Alzheimer\u27s Disease

Increased Alzheimer’s disease (AD) risk has previously been associated with a SNP called rs610932 near the gene MS4A6A. The goal of this experiment was to quantify the expression of two MS4A6A isoforms in the brains of AD and non-AD subjects, particularly as a function of rs610932 genotype. According to an article titled “Alzheimer’s Disease Susceptibility Variants in the MS4A6A Gene are Associated with Altered Levels of MS4A6A Expression in Blood”, MS4A6A has four different isoforms that have been reported to be differentially expressed in the blood of AD subjects compared to non-AD subjects (Petroula et al., 2014). After statistically analyzing the association between two of the MS4A6A variants, Isoform 6 (total MS4A6A transcript) and a variant, Isoform 4, and rs610932 using AD status and microglial expression as independent variables, we found significant expression differences in AD and non-AD subjects in the brain for the Isoform 4. We did not detect significant expression differences for Isoform 6 in AD subjects, nor did we find significant expression differences in either isoform as a function of the rs610932 SNP. These results are in contrast to previous findings that suggested a significant expression difference due to rs610932 in whole blood (Petroula et al., 2014). In summary, further work is necessary to understand how rs610932 modulates MS4A6A to alter AD risk

Role of the teacher aide in the secondary school

This research paper is primarily concerned with the teacher aide programs, as they now exist, with a view to laying the basis for a teacher aide program in a specific situation. Specific aspects will be: 1). Reporting and analyzing some of the current literature available concerning paid teacher aide programs in the secondary school; 2). Attempting to define the role of the teacher aide in a secondary school; 3). Examining the data concerning teacher aides in the secondary school reading programs as reported in response to questionnaires sent to the twenty cities with the highest population in the United States

How Bandwidth Selection Algorithms Impact Exploratory Data Analysis Using Kernel Density Estimation

Exploratory data analysis (EDA) is important, yet often overlooked in the social and behavioral sciences. Graphical analysis of one's data is central to EDA. A viable method of estimating and graphing the underlying density in EDA is kernel density estimation (KDE). A problem with using KDE involves correctly specifying the bandwidth to portray an accurate representation of the density. The purpose of the present study is to empirically evaluate how the choice of bandwidth in KDE influences recovery of the true density. Simulations were carried out that compared five bandwidth selection methods [Sheather-Jones plug-in (SJDP), Normal rule of thumb (NROT), Silverman's rule of thumb (SROT), Least squares cross-validation (LSCV), and Biased cross-validation (BCV)], using four true density shapes (Standard Normal, Positively Skewed, Bimodal, and Skewed Bimodal), and eight sample sizes (25, 50, 75, 100, 250, 500, 1000, 2000). Results indicated that overall SJDP performed best. However, this was specifically true for samples between 250 and 2,000. For smaller samples (N = 25 to 100), SROT performed best. Thus, either the SJDP or SROT is recommended depending on the sample size

Protein Dynamics and Entropy: Implications for Protein-Ligand Binding

The nature of macromolecular interactions has been an area of deep interest for understanding many facets of biology. While a great deal of insight has been gained from structural knowledge, the contribution of protein dynamics to macromolecular interactions is not fully appreciated. This plays out from a thermodynamic perspective as the conformational entropy. The role of conformational entropy in macromolecular interactions has been difficult to address experimentally. Recently, an empirical calibration has been developed to quantify the conformational entropy of proteins using solution NMR relaxation methods. This method has been demonstrated in two distinct protein systems. The goal of this work is to expand this calibration to assess whether conformational entropy can be effectively quantified from NMR-derived protein dynamics. First, we demonstrate that NMR dynamics do not correlate well between the solid and solution states, suggesting that the relationship between the conformational entropy of proteins is limited to solution state-derived NMR dynamics. We hypothesize that this may be partially due to the role of hydration of the protein in its dynamics. Next, we expand our empirical calibration to over 30 distinct protein systems and demonstrated that the relationship between NMR dynamics and conformational entropy is both robust and general. Furthermore, we demonstrate that conformational entropy plays a significant role in macromolecular interactions. Using our empirical calibration, we then look to address if conformational entropy could be an important contribution to drug design. The latter process is often a brute force approach, and subsequent optimization of initial drug candidates is often a guess and check process. In silico drug design was thought to offer a more efficient and rational approach, but often relies on static structures. This minimizes or completely neglects the role that conformational entropy may play in binding. Here we experimentally determine the role of conformational entropy in the drug target p38a MAPK in binding to two potent inhibitors. We demonstrate evidence that conformational entropy may represent a tunable parameter in affinity optimization of lead compounds. This has important implications for lead optimization and strongly suggests that the role of conformational entropy be considered in drug design efforts

Application of Check In-Check Out as a Targeted Intervention to Increase Appropriate Behavior in At-Risk High School Students

The purpose of the present study was to evaluate the effectiveness of Check In-Check Out (CICO) in increasing appropriate behavior and decreasing disruptive behavior of three students in south Mississippi who were referred for behavioral problems, a multiple baseline across students design was employed. Target students\u27 levels of appropriate behavior and frequency of disruptive behavior over time were compared through evaluation of daily behavior report card (DBRC) point data and rates of office discipline referrals (ODRs). Treatment integrity was assessed. The current study serves as one of the few studies in the CICO literature to (a) implement ClCO in a high school setting, (b) examine appropriate behavior through the use of DBRC, (c) evaluate treatment integrity for all days of CICO implementation, and (d) set point goals based on baseline performance. Furthermore, challenges in implementation and possible solutions are discussed. Results suggest that CICO may be a viable intervention, resulting in increases in appropriate behavior and decreases in disruptive behaviors across all participants

Evaluation of Performance-Based and Pre-set Conventional Criterion for Reinforcement in Check In-Check Out

The purpose of the present study was to compare the effectiveness of two methods of criterion-setting, performance-based or pre-set conventional, as evidenced by improvements in children’s behavior. Participant behavior was evaluated through teacher reports of appropriate behavior and observed academically engaged behavior as well as decreases in problem behavior and disruptive behavior. Eight elementary school students in a Southeastern town referred for exhibiting behavior problems served as participants in addition to their teachers. The effects of the different methods of criterion setting on the dependent variables were evaluated. Teacher ratings of appropriate behavior were assessed through evaluation of Daily Behavior Report Card (DBRC) point data. Direct observations were conducted to determine target students’ and control peers’ levels of observed appropriate behavior and problem behavior. Disruptive behavior was evaluated as the frequency of office discipline referrals (ODRs). Treatment integrity was assessed through direct observations as well as a review of permanent products. Acceptability was assessed for adult and child participants. The current study serves as one of the few studies in the Check In-Check Out (CICO) literature to (a) examine various methods of criterion setting, specifically Performance-Based methodology; (b) present teacher ratings of appropriate behavior through use of DBRCs; (c) conduct direct observations of target students and control peers’ appropriate behavior; and (d) evaluate treatment integrity for all days of CICO implementation with supplementary direct observations of treatment integrity. Results suggest that CICO was effective in improving participant behavior without providing evidence of the superiority of either method of criterion setting

Should Louisville Build a Dual Tenant or Single Tenant Arena?

The purpose of this research design was to make recommendations to Louisville Metro Council Members, members of the Kentucky General Assembly from Jefferson County and Louisville Metro Mayor Jerry Abramson on the potential revenue and economic impact a potential franchise of the National Basketball Association (NBA) could have on the proposed Louisville Arena Project and the city of Louisville. Research in the literature review showed that stadiums, arenas and professional teams are poor investments by communities. Despite the research, the new Louisville Arena is going to be built because the Kentucky General Assembly included $75-million in bond financing for the Louisville Arena and the city of Louisville has already pledged their bonding capacity to help pay a third of the cost. One of the major components lacking is research to show if a professional team can help subsidize an arena that is already in existence and as a result, making it a “dual-use” facility. The proposed Louisville Arena project must have 113 dates annually to operate at a “break even” level. Currently, 138 events take place in Freedom Hall annually according to the Leib Group, consultants for the new Louisville Arena project, but only a portion of those events are expected to move to the new arena when it opens. As a result, Louisville lawmakers are going to need to start looking at ways to subsidize the debt service obligations and the question this study addresses is if an NBA team could do just that. The results of a study by the University of Memphis show that 58Comparisons of the proposed Louisville Arena to NBA arenas located in cities of a similar market size to Louisville indicate that the proposed single-use facility is adequate enough to serve as a dual-use facility. Results also revealed that if an NBA team were attracted to the city of Louisville,$24 million (available in Table 7) in new revenues could be generated for the city of Louisville and the Louisville Arena Authority by having a dual-use facility. This is largely due to the NBA providing new “entertainment” to the community because an NBA team draws from a larger market base. There is also the reality that currently not a single major-league professional team of any type in the state of Kentucky. This contrasts with the University of Louisville men’s and women’s basketball teams which would simply move the entertainment money from one location (Freedom Hall) to another location in downtown Louisville. Incentives and the probability of attracting a potential NBA franchise to Louisville were addressed, as was a discussion on how the arena would still be able to issue tax-exempt bonds, even if one of the “primary” tenants is a privately held professional basketball team. Recommendations were made based on the results of the economic and revenue impact analysis. The recommendations provide a different perspective on how an NBA team can move into a community and help bring in new revenue and visitors

THE ROLE OF MELATONIN IN BIOLOGICAL RHYTHMS OF SONGBIRDS

In vertebrates, melatonin is a hormone that is produced and secreted at night and inhibited by light. This unique “darkness-only” expression profile makes it an intellectually appealing candidate for a means of transmitting temporal information to an individual, both time of day and time of year. In passerine birds, “time of day” information is certainly transmitted via melatonin secretion. The primary producer of systemic melatonin in this family of birds is the pineal gland, and surgical removal of it causes a bird to become arrhythmic in constant conditions. I find that as pinealectomized house sparrows (Passer domesticus) become behaviorally arrhythmic in extended constant darkness the molecular clock in their peripheral tissues largely continues to cycle absent its hypothesized synchronizing cues from the pineal gland. This suggests that the peripheral tissues are either autonomous or that there is a possible secondary circadian oscillator that synchronizes these tissues, such as the avian suprachiasmatic nucleus. In passerine birds, “time of year” information is not transmitted via melatonin secretion to the primary gonads, unlike the case in seasonally breeding mammals. The duration of melatonin, longer in the winter and shorter in the spring as the photoperiod changes with the seasons, does affect secondary sexual characteristics, such as the vocal behavior of birds and the size of the associated nuclei in the brain. I find that long durations of melatonin are sufficient in preventing the photoperiodic expansion of vocal state in male house sparrows. This vocal state change in males consists of the development of a dawn and dusk chorus, as well as a switch from a vocal subtype associated with the wintertime birds flocking together to one of mate attraction and territory defense. This dynamic was independent of the size of the gonads, which were consistent those of photostimulated males. I also investigate this vocal state change in outdoor captive sparrows. This vocal state change is also present in female house sparrows, although unlike in male birds, the presence of absence of the pineal gland does not affect the timing of their vocalizations. Further, I investigate the ability for rhythmic presentations of vocalizations to influence the circadian clock, in zebra finches, Taeniopygia guttata. Aural cues have been shown to act as a weak external cue for entraining a passerine bird’s circadian clock. I presented various permutations of zebra finch vocalization: a single song played repeatedly, the same song played reversed, random tones, and live monitoring of a breeding colony entrained to a light-dark cycle. The live monitoring was the strongest aural cue, and more generally it appears that novelty and context enhance the effect of audio cues on the circadian clock. These experiments in sum suggest a role of melatonin in gating the seasonal expression of vocalization behavior in house sparrows. In male birds, a component of the seasonal dynamic is the development of a multimodal rhythm to when during the day the birds vocalize as the days lengthen consistent with spring, suggesting that the circadian clock may be involved with this diel variability. Additionally, this vocal behavior can also feedback onto the circadian clock. The pineal gland and its primary hormone melatonin function, in part, to regulate complex behavioral rhythms in passerine birds