Metabolic Targeting Of Malignant Glioma: Modulation Of Glycolytic Flux By Erythropoietic Factors

Introduction: Malignant glioma display a highly glycolytic phenotype where the tumors flux glucose to lactic acid independent of oxygen concentration ( aerobic glycolysis ). This altered phenotype is facilitated by expression of primarily fetal enzyme isoforms in these malignant tumors. The end-product lactic acid is rapidly expelled from the cytosol by selective monocarboxylate transporters expressed on the plasma membrane. GATA response element islands are present on the promoter of glioma lactate transporter genes, and GATA-1 has been shown to be over-expressed in glioblastoma. Our long-term goal is to inhibit glioma proliferation by indirectly down-regulating GATA-1 to inhibit glycolysis. (Colen et al., 2006; Mathupala et al., 2007; Mathupala et al., 2004) Methods: We have engineered U87-MG glioblastoma tumor cell lines to either over-express (via viral promoter based vectors) or silence (using siRNA inducible vector systems) GATA-1. Cell proliferation was assessed via both MTT assay and cell cycle analysis. Luciferase based reporter gene analysis was utilized to identify regulation of lactate transporter promoter by GATA-1. Results: Western blot analysis indicated up- and down-regulation of GATA-1 via the appropriate vector system. Up- or down-regulation of GATA-1 either enhanced or reduced the proliferative rate and the lactate transporter promoter activity. Conclusions: Regulation of GATA-1 directly impacts glycolytic metabolic flux and proliferation of malignant glioma. Thus, small molecule drugs against GATA-1 may be used as an adjuvant therapy for metabolic targeting of malignant glioma

Do We Need a New Legal Framework for Fighting Non-Conventional Wars? The International Law of War, Human Rights and the Global Fight Against Extremism and Terrorism

This paper examines the existing legal framework for fighting violent extremism and terrorism. Highlighting the inherent limitations of the current International Law of War in dealing with the growing challenges posed by terrorists and violent extremist groups, the paper discusses the problem facing military commanders, security agents, state actors and the international community in confronting extremist groups while upholding human rights values and respecting the law of war. The paper poses the question as to whether the current legal framework for dealing with extremist groups is sufficient without contravening the essential provisions and ethos of the International Law of War and Human Rights. Using examples, the paper examines how extremist groups flagrantly disregard the rule of law and disrespect human rights in their campaign of terror. The paper also notes instances in which the current Western strategy in fighting terrorism may be viewed or considered as conflicting with human rights and international law

Evaluating Density Forecasts

We propose methods for evaluating density forecasts. We focus primarily on methods that are applicable regardless of the particular user's loss function. We illustrate the methods with a detailed simulation example, and then we present an application to density forecasting of daily stock market returns. We discuss extensions for improving suboptimal density forecasts, multi-step-ahead density forecast evaluation, multivariate density forecast evaluation, monitoring for structural change and its relationship to density forecasting, and density forecast evaluation with known loss function.

Evaluating density forecasts

The authors propose methods for evaluating and improving density forecasts. They focus primarily on methods that are applicable regardless of the particular user's loss function, though they take explicit account of the relationships between density forecasts, action choices, and the corresponding expected loss throughout. They illustrate the methods with a detailed series of examples, and they discuss extensions to improving and combining suboptimal density forecasts, multistep-ahead density forecast evaluation, multivariate density forecast evaluation, monitoring for structural change and its relationship to density forecasting, and density forecast evaluation with known loss function.Forecasting

State vs non-state armed groups - a political economy of violence

The early 21st century has witnessed the rise in violent extremism with groups such as Al Qaeda and Islamic State of Iraq and the Levant (ISIL) in the Middle East, the Boko Haram in West Africa, and Al Shabaab in East Africa. The activities of these and other non-state armed groups have created a general state of panic and fear that is spreading beyond their areas of operation to other parts of the political world. Rather than diminishing the influence of these groups, the states' counter extremism strategies seem to be further fuelling the extremism and creating new waves of violence that threatens global security and undermines the very essence of our collective wellbeing. This paper examines the socio-economic and political environment in which these armed groups have thrived and poses the question as to whether the failure of politics and development are to blame for the rise of extremism. The paper proposes a new approach to combating extremism that involves re-connecting people with politics and development. The basic contention of this paper is that there has been a failure of the state to satisfy the wellbeing of its citizens. The paper provides an explanation of, but by no means a justification of, the use of violent extremism in the early 21st century

A Creationist Perspective on the Origin of Pathogenic Vibrio Cholerae and Vibrio Cholerae Toxin (CT)

Many microbial pathogens and toxins exhibit elaborate mechanisms of engagement with mammalian cell structure and cell biochemistry. For instance, some toxins gain entrance into cells using exquisite secretory devices and, once inside cells, interact in very specific ways with intracellular membrane trafficking factors and cell signaling components. Because many microbial pathogens and their associated toxins appear to be created to interact with human cells, they are difficult to explain within the context of a “good creation.” In this paper, we examine the pathogenic role of V. cholerae, the cholera toxin (CT) and other associated virulence factors, and their origin in the context of the creation model. We examine the literature and use methods of genomic comparison to investigate the origin of CT and the corresponding origin of cholera. Our results are consistent with a model of nonpathogenic function for CT prior and even after the Fall. We suggest that the originally beneficial function of CT has been subsequently modified by the presence of phages and mobile genetic elements

A fixed point theorem for the infinite-dimensional simplex

We define the infinite dimensional simplex to be the closure of the convex hull of the standard basis vectors in R^infinity, and prove that this space has the 'fixed point property': any continuous function from the space into itself has a fixed point. Our proof is constructive, in the sense that it can be used to find an approximate fixed point; the proof relies on elementary analysis and Sperner's lemma. The fixed point theorem is shown to imply Schauder's fixed point theorem on infinite-dimensional compact convex subsets of normed spaces.Comment: 8 pages; related work at http://www.math.hmc.edu/~su/papers.htm

Diplomacy and the politics of fear: the 21st century challenges to the theory and practice of Diplomacy and International Relations

Conflicts, political unrest, mass migration and the rise of violent extremism by non-state actors are features that have characterized the early 21st century. A huge challenge to world peace and security is posed by volatile economic and political conditions around the world. This situation has led to a growing tension in many inter-state relations which arguably has underpinned the rise of groups such as Al Qaeda and Islamic State of Iraq and the Levant (ISIL) in the Middle East, the Boko Haram in West Africa, and Al Shabaab in East Africa. Arguably, there is a growing sense of fear and unease in every sphere of social, economic and political life. More than at any other time in human history, the future seems uncertain. Relationships and trusts between states and their citizens are breaking down; relations, mutual cooperation and connections between states are under strain; there is growing sense of disillusionment by the governed of the ability of governments and mainstream political establishments to address their concerns and meet their needs. The feeling of uncertainty and general fear for the future is real. While these may not necessarily be universally held views, there is a growing indication that people and communities around the world are feeling dissatisfied and may be threatened by mainstream political systems. Just when it is most needed, diplomacy and diplomatic practice seem to be taking the back seat in the face of growing conflicts. This conference examines the socio-economic and political environment that creates social and political discontent, political apathy, the weakening of inter-state relations, and the general sense of fear

Bacteriophages as Beneficial Regulators of the Mammalian Microbiome

Much of the research on viruses has concentrated on their disease causing ability. The creation model biomatrix theory predicts that viruses play a beneficial role in cells and organisms. In this report we present a new theory which proposes that mammalian phages (bacteriophages), the most abundant organism associated with mammals, guard and regulate growth of the mammalian microbiome. We base this theory on nearly a century of published evidence that demonstrates that phage can insert into the bacterial genome and cover the surface of bacteria. We propose that this “cloaking” of the bacterial cell surface is an elegant mechanism whereby the normal flora bacteria are protected from immune detection and pathogenic bacteria can be directly lysed by the same phage. Additionally, both phage genome integration and cloaking can be used to prevent normal flora bacteria from conversion to a pathogenic state. Further support for the phage cloaking aspect of our theory has been demonstrated in recent studies which show that phage proteins bind specifically to microbial-associated molecular patterns (MAMPs), which are known to be the major ligands that activate the mammalian immune system. Although these phenomena have been documented separately over decades, we postulate for the first time that these functions work together to promote the integrity of the mammalian microbiome