Rho GTPases as therapeutic targets in Alzheimer’s disease

The progress we have made in understanding Alzheimer’s disease (AD) pathogenesis has led to the identification of several novel pathways and potential therapeutic targets. Rho GTPases have been implicated as critical components in AD pathogenesis, but their various functions and interactions make understanding their complex signaling challenging to study. Recent advancements in both the field of AD and Rho GTPase drug development provide novel tools for the elucidation of Rho GTPases as a viable target for AD. Herein, we summarize the fluctuating activity of Rho GTPases in various stages of AD pathogenesis and in several in vitro and in vivo AD models. We also review the current pharmacological tools such as NSAIDs, RhoA/ROCK, Rac1, and Cdc42 inhibitors used to target Rho GTPases and their use in AD-related studies. Finally, we summarize the behavioral modifications following Rho GTPase modulation in several AD mouse models. As key regulators of several AD-related signals, Rho GTPases have been studied as targets in AD. However, a consensus has yet to be reached regarding the stage at which targeting Rho GTPases would be the most beneficial. The studies discussed herein emphasize the critical role of Rho GTPases and the benefits of their modulation in AD

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Non-affirmative Theory of Education as a Foundation for Curriculum Studies, Didaktik and Educational Leadership

This chapter presents non-affirmative theory of education as the foundation for a new research program in education, allowing us to bridge educational leadership, curriculum studies and Didaktik. We demonstrate the strengths of this framework by analyzing literature from educational leadership and curriculum theory/didaktik. In contrast to both socialization-oriented explanations locating curriculum and leadership within existing society, and transformation-oriented models viewing education as revolutionary or super-ordinate to society, non-affirmative theory explains the relation between education and politics, economy and culture, respectively, as non-hierarchical. Here critical deliberation and discursive practices mediate between politics, culture, economy and education, driven by individual agency in historically developed cultural and societal institutions. While transformative and socialization models typically result in instrumental notions of leadership and teaching, non-affirmative education theory, previously developed within German and Nordic education, instead views leadership and teaching as relational and hermeneutic, drawing on ontological core concepts of modern education: recognition; summoning to self-activity and Bildsamkeit. Understanding educational leadership, school development and teaching then requires a comparative multi-level approach informed by discursive institutionalism and organization theory, in addition to theorizing leadership and teaching as cultural-historical and critical-hermeneutic activity. Globalisation and contemporary challenges to deliberative democracy also call for rethinking modern nation-state based theorizing of education in a cosmopolitan light. Non-affirmative education theory allows us to understand and promote recognition based democratic citizenship (political, economical and cultural) that respects cultural, ethical and epistemological variations in a globopolitan era. We hope an American-European-Asian comparative dialogue is enhanced by theorizing education with a non-affirmative approach

The association of psychiatric comorbidity and use of the emergency department among persons with substance use disorders: an observational cohort study

<p>Abstract</p> <p>Background</p> <p>Psychiatric and substance use problems are commonly found to be contributing factors to frequent Emergency Department (ED) use, yet little research has focused on the association between substance use and psychiatric comorbidity. This study assesses the association of a psychiatric comorbidity on (ED) use among patients with substance use disorders (SUDs).</p> <p>Methods</p> <p>The study focuses on 6,865 patients who were diagnosed with SUDs in the ED of a large urban hospital in the southern United States from January 1994 – June 1998. Patients were grouped by type of substance use disorder. After examining frequency of visits by diagnosis, the sample was assigned to the following groups–alcohol dependence (ICD9 = 303), alcohol abuse (ICD9 = 305.0), cocaine dependence/abuse (ICD9 = 304.2, 305.6), and polysubstance/mixed use (ICD9 = 305.9). A patient was classified with psychiatric comorbidity if a psychiatric diagnosis appeared during any of the patient's visits. The following psychiatric diagnoses were included–schizophrenia/psychoses, bipolar disorder, depression, anxiety, and dementia (ICD-9 codes available upon request).</p> <p>Results</p> <p>Patients with SUDs and psychiatric comorbidity had significantly higher mean number of ER visits (mean = 5.2 SD = 8.7) than SUD patients without psychiatric comorbidity (mean = 2.5, SD = 3.7). In logistic regressions predicting several categorizations of heavier use of the ED (either 4+, 8+, 12+, 16+, or 20+ visits over the span of the study) SUD patients with psychiatric comorbidity had adjusted odds ratios of 3.0 to 5.6 (reference group = patients with SUDs but no psychiatric comorbidity). This association was found across all substance use diagnostic categories studied, with the strongest relationship observed among patients with cocaine disorders or alcohol dependence.</p> <p>Conclusion</p> <p>The results provide further support for the notion that the ED could and should serve as an important identification site for cost-effective intervention.</p