Relevance of CD40/CD40L downstream pathways to Alzheimer's disease

The amyloid cascade hypothesis places amyloid-β at the origin of Alzheimer's disease (AD). Amyloid-β (Aβ) is the product of the sequential cleavage of the amyloid precursor protein (APP) by the enzymes β- and γ-secretases. An inflammatory component to AD has been suggested in association with CD40 (a member of the tumor necrosis factor receptor superfamily (TNFRS) and its cognate ligand CD40L. In this study, I hypothesized that the neutralization of pro-inflammatory cytokines produced downstream of CD40/CD40L interaction would reduce APP processing. I also hypothesized that blocking the binding of different adaptor proteins to CD40 by mutating its cytoplasmic tail would result in significant reduction of the APP metabolites: Aβ, sAPPβ, sAPPα, CTFβ and CTFα. ^ Treatment with CD40L of human embryonic kidney cells over-expressing both APP and CD40 (HEK/APPsw/CD40) significantly increased levels of the cytokine granulocyte macrophage colony stimulating factor (GM-CSF). Neutralizing antibodies against GM-CSF mitigated the CD40L-induced production of Aβ in these cells. Treatment of the HEK/APPsw/CD40 cells with recombinant GM-CSF significantly increased Aβ levels. GM-CSF receptor gene silencing with shRNA significantly reduced Aβ levels to below base line in non-stimulated HEK/APPsw/CD40 cells. Silencing of the GM-CSF receptor also decreased APP endocytosis (therefore reducing the availability of APP to be cleaved in the endosomes). ^ Using CD40 mutants, I show that CD40L can increase levels of Aβ(1-40), Aβ(1-42), sAPPβ, sAPPα and CTFβ independently of TRAF signaling. TRAFs had been shown to be necessary for most CD40/CD40L-dependent signaling. An increase in mature/immature APP ratio after CD40L treatment of CD40wt and CD40-mutant cells was observed, reflecting alterations in APP trafficking. CD4OL treatment of a neuroblastoma cell line over-expressing CTFβ suggested that CD40L affected γ-secretase activity. Inhibition of γ-secretase activity significantly reduced sAPPβ levels in the CD40L treated HEK/APPsw CD40wt and the CD40-mutant cells. The latter suggests CD40/CD40L interaction primarily acts on γ-secretase and affects β-secretase via a positive feedback mechanism. ^ Taken together, the results of this dissertation suggest that GM-CSF operates downstream of CD40/CD40L interaction and that GM-CSF modulates Aβ production by influencing APP trafficking. Moreover, the data presented suggest that CD40/CD40L interaction can modulate APP processing via a mechanism independent of TRAF signaling. ^

Role of calcium in inflammation: Relevance to Alzheimer's disease

Alzheimer’s disease (AD) is neuropathologically characterized by excessive beta -amyloid (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau in the brain. Although the etiology of genetic cases of AD has been attributed to mutations in presenilin and amyloid precursor protein (APP) genes, in most sporadic cases of AD, the etiology is still unknown and various predisposing factors could contribute to the pathology of AD. Predominant among these possible predisposing factors that have been implicated in AD are age, hypertension, traumatic brain injury, diabetes, chronic neuroinflammation, alteration in calcium levels and oxidative stress. Since both inflammation and altered calcium levels are implicated in the pathogenesis of AD, we wanted to study the effect of altered levels of calcium on inflammation and the subsequent effect of selective calcium channel blockers on the production of pro-inflammatory cytokines and chemokines. Our hypothesis is that Aβ, depending on it conformation, may contribute to altered levels of intracellular calcium in neurons and glial cells. We wanted to determine which conformation of Aβ was most pathogenic in terms of increasing inflammation and calcium influx and further elucidate the possibility of a link between altered calcium levels and inflammation. In addition, we wanted to test whether calcium channel blockers could inhibit the inflammation mediated by the most pathogenic form of Aβ, by antagonizing the calcium influx triggered by Aβ. Our results in human glial and neuronal cells demonstrate that the high molecular weight oligomers are the most potent at stimulating the release of pro-inflammatory cytokines IL-6 and IL-8 as well as increasing intracellular levels of calcium compared to other conformations of Aβ. Further, L-type calcium channel blockers and calmodulin kinase inhibitors are able to significantly reduce the levels of IL-6 and IL-8. These results suggest that Aβ-induced alteration of intracellular calcium levels contributes to its pro-inflammatory effect.

The Relevance of Marxist Academics

This commentary examines the relationship between a Marxist scholar and the institutional and societal environment of the university. The focus is on how a Marxist academic navigates the social, economic and political aspects of the university while attempting to maintain a commitment to class analysis and Marxism as political practice.

Relevance of the community college curriculum to the international student

The purpose of this study was to ascertain the perception of the level of satisfaction that international students have regarding the services and the relevance of the curriculum offered at Miami-Dade Community College. Trends and issues at universities and community colleges in providing services and an international curriculum for foreign students are outlined. Focus is on characteristics, personal and career needs as well as needs of national development for the students' countries. A sample of students from four developing nations was selected to qualitatively and quantitatively determine their level of satisfaction. The nations are the Bahamas, Colombia, Haiti and Pakistan. Students responses were recorded through group interviews, four personal interviews, an open ended questionnaire and a Likert scaled survey questionnaire. Matrix charts, mean calculations and one way analysis of variance were used to analyze data collected. Country of origin and major program of study were the variables used for statistical analysis. Information gathered through qualitative research presented a variety of perspectives and responses, both positive and negative. Students supplied specific examples of experiences and insights to help explain their various perceptions. Statistically, there were no significant differences between the variables of country of origin and major program of study regarding program services and relevance of the curriculum. Implications and recommendations for community college programs were outlined.

What more can we learn from early learning theory? The contemporary relevance for behaviour change interventions

Peer reviewed

What more can we learn from early learning theory? The contemporary relevance for behaviour change interventions

Peer reviewed

Regulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) : relevance to diabetic vasculopathy

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Synthesis of heterocyclic compounds of medicinal relevance

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Asymmetric 3D video coding based on regions of perceptual relevance

This dissertation presents a study and experimental research on asymmetric coding of stereoscopic video. A review on 3D technologies, video formats and coding is rst presented and then particular emphasis is given to asymmetric coding of 3D content and performance evaluation methods, based on subjective measures, of methods using asymmetric coding. The research objective was de ned to be an extension of the current concept of asymmetric coding for stereo video. To achieve this objective the rst step consists in de ning regions in the spatial dimension of auxiliary view with di erent perceptual relevance within the stereo pair, which are identi ed by a binary mask. Then these regions are encoded with better quality (lower quantisation) for the most relevant ones and worse quality (higher quantisation) for the those with lower perceptual relevance. The actual estimation of the relevance of a given region is based on a measure of disparity according to the absolute di erence between views. To allow encoding of a stereo sequence using this method, a reference H.264/MVC encoder (JM) has been modi ed to allow additional con guration parameters and inputs. The nal encoder is still standard compliant. In order to show the viability of the method subjective assessment tests were performed over a wide range of objective qualities of the auxiliary view. The results of these tests allow us to prove 3 main goals. First, it is shown that the proposed method can be more e cient than traditional asymmetric coding when encoding stereo video at higher qualities/rates. The method can also be used to extend the threshold at which uniform asymmetric coding methods start to have an impact on the subjective quality perceived by the observers. Finally the issue of eye dominance is addressed. Results from stereo still images displayed over a short period of time showed it has little or no impact on the proposed method.

US-Based Food and Agricultural Value Chains and Their Relevance to Healthy Diets.

This article examines the structure and health implications of two industries, chicken and tomatoes, that play prominent roles in US food and agricultural competitiveness. Both industries have become more concentrated over time, with powerful "lead firms" driving geographical, technological, and marketing changes. Overall, a processed food revolution has taken place in agricultural products that transforms the types of food and dietary options available to consumers. The nature of contemporary food and agricultural value chains affects the strategies and policies that can be effectively employed to address major health goals such as improved nutrition, food safety, and food security.

The quality of financial information in the extractive industries: a value relevance analysis

The extractive industry is characterized by high levels of risk and uncertainty. These attributes create challenges when applying traditional accounting concepts (such as the revenue recognition and matching concepts) to the preparation of financial statements in the industry. The International Accounting Standards Board (2010) states that the objective of general purpose financial statements is to provide useful financial information to assist the capital allocation decisions of existing and potential providers of capital. The usefulness of information is defined as being relevant and faithfully represented so as to best aid in the investment decisions of capital providers. Value relevance research utilizes adaptations of the Ohlson (1995) to assess the attribute of value relevance which is one part of the attributes resulting in useful information. This study firstly examines the value relevance of the financial information disclosed in the financial reports of extractive firms. The findings reveal that the value relevance of information disclosed in the financial reports depends on the circumstances of the firm including sector, size and profitability. Traditional accounting concepts such as the matching concept can be ineffective when applied to small firms who are primarily engaged in nonproduction activities that involve significant levels of uncertainty such as exploration activities or the development of sites. Standard setting bodies such as the International Accounting Standards Board and the Financial Accounting Standards Board have addressed the financial reporting challenges in the extractive industry by allowing a significant amount of accounting flexibility in industryspecific accounting standards, particularly in relation to the accounting treatment of exploration and evaluation expenditure. Therefore, secondly this study examines whether the choice of exploration accounting policy has an effect on the value relevance of information disclosed in the financial reports. The findings show that, in general, the Successful Efforts method produces value relevant information in the financial reports of profitable extractive firms. However, specifically in the oil & gas sector, the Full Cost method produces value relevant asset disclosures if the firm is lossmaking. This indicates that investors in production and non-production orientated firms have different information needs and these needs cannot be simultaneously fulfilled by a single accounting policy. In the mining sector, a preference by large profitable mining companies towards a more conservative policy than either the Full Cost or Successful Efforts methods does not result in more value relevant information being disclosed in the financial reports. This finding supports the fact that the qualitative characteristic of prudence is a form of bias which has a downward effect on asset values. The third aspect of this study is an examination of the effect of corporate governance on the value relevance of disclosures made in the financial reports of extractive firms. The findings show that the key factor influencing the value relevance of financial information is the ability of the directors to select accounting policies which reflect the economic substance of the particular circumstances facing the firms in an effective way. Corporate governance is found to have an effect on value relevance, particularly in the oil & gas sector. However, there is no significant difference between the exploration accounting policy choices made by directors of firms with good systems of corporate governance and those with weak systems of corporate governance.

Regulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) : relevance to diabetic vasculopathy

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Synthesis of heterocyclic compounds of medicinal relevance

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Transformative Learning Theory and Its Relevance to Managing Group Dynamics in a Competitive Work Environment

In any environment, group dynamics would exist. How we deal with it in a competitive work environment defines who we are using transformative learning. This paper provides useful information from a number of theorists who share perspectives on the complex nature of groups.