The Design And Synthesis Of Allosteric Effectors Of Carbon Monoxide Binding To Hemoglobin

The development of small molecule allosteric inhibitors of carbon monoxide (CO) binding to hemoglobin (Hb) is important for the treatment of CO poisoning. We have found that the synthetic peptide IRL 2500 leads to inhibition of CO binding, but with concomitant hemolytic activity. We describe herein the design, synthesis and biological evaluation of analogs of IRL 2500 that inhibit CO binding without hemolysis. The most potent compounds that we have prepared to date contain heteroaromatic biaryls in place of the biphenyl moiety of IRL 2500. These compounds show improved solubility and reduced hemolytic activity. We also describe the synthesis of conformationally constrained analogs of IRL 2500 based on a piperazine-derived scaffold

Exploring the Relationship between Long-Term Memory and Attention through Attentional Templates

It is assumed that the contents of visual working memory (VWM) guide attention. This notion has been challenged by work which has demonstrated that multiple searches for the same target changes contralateral delay activity (CDA), an event-related potential that is the putative marker of the amount of information maintained in VWM. It has been suggested that the disappearance of the CDA with an invariable target marks the transfer of the attentional template from VWM storage to long-term memory (LTM) storage. Therefore, LTM may guide attention in many situations where it has previously been assumed that VWM guides attention. However, while the transfer of attentional template from VWM to LTM is demonstrated through a decrease in the amplitude of the CDA, this shift has not been accompanied by a corresponding behavioral change in response times. The purpose of the present study was to test the hypothesis that a LTM template leads to faster performance than a VWM template (the LTM template hypothesis). Two experiments were conducted to explore this hypothesis. In Experiment 1, the LTM template hypothesis was examined by comparing performance between two different groups of subjects: the first group searched for a target that changed on every trial (variable) while the second group searched for a target that was invariable across trials. In Experiment 2, one group of subjects searched for both the variable and invariable targets. The results showed that a LTM template (invariable target search) leads to faster performance than a VWM template (variable target search). Roughly six times as many trials were required for an effect on performance compared to the number of trials required for an effect in CDA amplitude. Eye tracking results suggest the change in performance is due to more efficient search initiation and target verification

Gaps in state funding mean that liberal cities in conservative states are more likely to lobby the federal government

When we hear the term 'lobbying' we tend to think mostly in terms of corporations and ideological groups working to influence policy outcomes at the state and federal level. But cities are often lobbyists too. In new research, Rebecca Goldstein and Hye Young You examine the causes and consequences of lobbying the federal government by American cities. They find that liberal cities in conservative states such as New Orleans, Tucson, and Houston were the most likely to lobby, a trend that they explain may be down to gaps between how much these cities and their states spend on public services and infrastructure

The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H\u3csub\u3e2\u3c/sub\u3e0\u3csub\u3e2\u3c/sub\u3e and plays an integral role in insulin signal transduction

Insulin stimulation of target cells elicits a burst of H2O2 that enhances tyrosine phosphorylation of the insulin receptor and its cellular substrate proteins as well as distal signaling events in the insulin action cascade. The molecular mechanism coupling the insulin receptor with the cellular oxidant-generating apparatus has not been elucidated. Using reverse transcription-PCR and Northern blot analyses, we found that Nox4, a homolog of gp91phox, the phagocytic NAD(P)H oxidase catalytic subunit, is prominently expressed in insulin-sensitive adipose cells. Adenovirus-mediated expression of Nox4 deletion constructs lacking NAD(P)H or FAD/NAD(P)H cofactor binding domains acted in a dominant-negative fashion in differentiated 3T3-L1 adipocytes and attenuated insulin-stimulated H2O2 generation, insulin receptor (IR) and IRS-1 tyrosine phosphorylation, activation of downstream serine kinases, and glucose uptake. Transfection of specific small interfering RNA oligonucleotides reduced Nox4 protein abundance and also inhibited the insulin signaling cascade. Overexpression of Nox4 also significantly reversed the inhibition of insulin-stimulated IR tyrosine phosphorylation induced by coexpression of PTP1B by inhibiting PTP1B catalytic activity. These data suggest that Nox4 provides a novel link between the IR and the generation of cellular reactive oxygen species that enhance insulin signal transduction, at least in part via the oxidative inhibition of cellular protein-tyrosine phosphatases (PTPases), including PTP1B, a PTPase that has been previously implicated in the regulation of insulin action

Structural Analyses of Two Inositol Metabolizing Enzymes

Thesis advisor: Mary F. RobertsMyo-inositol and its phosphorylated derivatives are found across all domains of life, and these molecules play crucial roles in a wide variety of cellular processes. While the biosynthesis of inositol is an evolutionarily conserved pathway, there are a wide variety of enzymes that use inositol and its derivatives as substrates. This thesis explores two such enzymes; a phosphatidylinositol- specific phospholipase C (PI-PLC) produced by Staphylococcus aureus, and AF2372, a dual action inositol monophosphatase/ fructose bisphosphatase produced by the Archaeoglobus fulgidus. At the outset of this work, the structure of the S. aureus PI-PLC was unknown, but some interesting biochemical properties about the enzyme had been observed. The structure of AF2372 had been reported, but a structure had not yet been solved in the presence of osmolytes known to thermoprotect the enzyme. Both the S. aureus PI-PLC and AF2372 catalyze the cleavage of phosphorylated inositol compounds, but share no mechanistic, structural, or taxonomical similarities. Protein crystallography is a powerful tool, and with it I have been able to study these two enzymes at a molecular level, providing insight into complex biological questions about each enzyme.Thesis (PhD) — Boston College, 2012.Submitted to: Boston College. Graduate School of Arts and Sciences.Discipline: Chemistry

The Best Democracy Money Can Buy: NCLB in Bush\u27s Neo-liberal Marketplace (a.k.a., Revisioning History: The Discourses of Equality, Justice and Democracy Surrounding NCLB)

With the landmark passage of No Child Left Behind (NCLB) in January 2002, a new era of accountability, standards, and sanctions have become solid fixtures in public education (see Cross, 2004; McGuinn, 2005; and McGuinn, 2006 for an extensive discussion of the evolution of standards in US public education). The implications of this federal mandate were viewed differently, depending upon the perspective of the viewer. Regardless, there has been and continues to be a great deal of skepticism regarding NCLB’s ability to change the educational experiences of children and youth, particularly those of poor and minority students (Fusarelli, 2004; Kantor & Lowe, 2006; Rogers & Oakes, 2005). Further, the political discourse surrounding NCLB has been very charged since its inception, with different camps supporting the legislation as an extension of the Brown decision (and hence, the realization of equality in US society), while others have decried it as discriminatory, marginalizing, and undemocratic (see for instance, Kozol, 2005; Paige, 2006; Slavin, 2006; and Stiefel, Schwartz, & Chellman, 2007 for examples of these different arguments). It is these arguments surrounding equality/equity, social justice, democracy (and education for democracy), and NCLB that this article will examine. Using the speeches of Secretaries of Education Roderick Paige and Margaret Spellings, we will illustrate how the federal government and NCLB, the federal education policy driving US public education, frames the notions of equality/equity, justice, and democracy to reflect the Administration’s conservative and market-driven ideologies. By engaging in an iterative process of critical discourse analysis, we will illustrate how the message conveyed regarding NCLB remains the same, even as the audience changes. As a result, the Bush Administration has been able to galvanize support across multiple communities, while simultaneously silencing opposition

Population sampling in longitudinal suverys

The paper questions the need for observational studies to achieve representativeness for real populations, in particular for longitudinal studies. It draws upon recent debates and argues for the need to distinguish scientific inference from population inference

Evaluating the provision of school performance information for school choice

We develop and implement a framework for determining the optimal performance metrics to help parents choose a school. This approach combines the three major critiques of the usefulness of performance tables into a natural metric. We implement this for 500,000 students in England for a range of performance measures. Using performance tables is strongly better than choosing at random: a child who attends the highest ex ante performing school within their choice set will ex post do better than the average outcome in their choice set twice as often as they will do worse