Genetic Studies Identify Critical Biomarkers and Refine the Classification of Malignant Gliomas

Gliomagenesis is driven by a complex network of genetic alterations and while the glioma genome has been a focus of investigation for many years; critical gaps in our knowledge of this disease remain. The identification of novel molecular biomarkers remains a focus of the greater cancer community as a method to improve the consistency and accuracy of pathological diagnosis. In addition, novel molecular biomarkers are drastically needed for the identification of targets that may ultimately result in novel therapeutics aimed at improving glioma treatment. Through the identification of new biomarkers, laboratories will focus future studies on the molecular mechanisms that underlie glioma development. Here, we report a series of genomic analyses identifying novel molecular biomarkers in multiple histopathological subtypes of glioma and refine the classification of malignant gliomas. We have completed a large scale analysis of the WHO grade II-III astrocytoma exome and report frequent mutations in the chromatin modifier, alpha thalassemia mental retardation x-linked (ATRX), isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), and mutations in tumor protein 53 (TP53) as the most frequent genetic mutations in low grade astrocytomas. Furthermore, by analyzing the status of recurrently mutated genes in 363 brain tumors, we establish that highly recurrent gene mutational signatures are an effective tool in stratifying homogeneous patient populations into distinct groups with varying outcomes, thereby capable of predicting prognosis. Next, we have established mutations in the promoter of telomerase reverse transcriptase (TERT) as a frequent genetic event in gliomas and in tissues with low rates of self renewal. We identify TERT promoter mutations as the most frequently mutated gene in primary glioblastoma. Additionally, we show that TERT promoter mutations in combination with IDH1 and IDH2 mutations are able to delineate distinct clinical tumor cohorts and are capable of predicting median overall survival more effectively than standard histopathological diagnosis alone. Taken together, these data advance our understanding of the genetic alterations that underlie the transformation of glial cells into neoplasms and we provide novel genetic biomarkers and multi – gene mutational signatures that can be utilized to refine the classification of malignant gliomas and provide opportunity for improved diagnosis.

RNA Virus Evolution: a Cross-scale, Disease Dynamic Perspective

RNA viruses are an important cause of global morbidity and mortality. The rapid evolutionary rates of RNA virus pathogens, caused by high replication rates and error-prone polymerases, can make the pathogens difficult to control. RNA viruses can undergo immune escape within their hosts and develop resistance to the treatment and vaccines we design to fight them. Understanding the spread and evolution of RNA pathogens is essential for reducing human suffering. In this dissertation, I make use of the rapid evolutionary rate of viral pathogens to answer several questions about how RNA viruses spread and evolve. To address each of the questions, I link mathematical techniques for modeling viral population dynamics with phylogenetic and coalescent techniques for analyzing and modeling viral genetic sequences and evolution. The first project uses multi-scale mechanistic modeling to show that decreases in viral substitution rates over the course of an acute infection, combined with the timing of infectious hosts transmitting new infections to susceptible individuals, can account for discrepancies in viral substitution rates in different host populations. The second project combines coalescent models with within-host mathematical models to identify driving evolutionary forces in chronic hepatitis C virus infection. The third project compares the effects of intrinsic and extrinsic viral transmission rate variation on viral phylogenies.

Theory and Practice in Sustainability Science: Influence of Urban Form on the Urban Heat Island and Implications for Urban Systems

As the world population continues to grow past seven billion people and global challenges continue to persist including resource availability, biodiversity loss, climate change and human well-being, a new science is required that can address the integrated nature of these challenges and the multiple scales on which they are manifest. Sustainability science has emerged to fill this role. In the fifteen years since it was first called for in the pages of Science, it has rapidly matured, however its place in the history of science and the way it is practiced today must be continually evaluated. In Part I, two chapters address this theoretical and practical grounding. Part II transitions to the applied practice of sustainability science in addressing the urban heat island (UHI) challenge wherein the climate of urban areas are warmer than their surrounding rural environs. The UHI has become increasingly important within the study of earth sciences given the increased focus on climate change and as the balance of humans now live in urban areas.

In Chapter 2 a novel contribution to the historical context of sustainability is argued. Sustainability as a concept characterizing the relationship between humans and nature emerged in the mid to late 20th century as a response to findings used to also characterize the Anthropocene. Emerging from the human-nature relationships that came before it, evidence is provided that suggests Sustainability was enabled by technology and a reorientation of world-view and is unique in its global boundary, systematic approach and ambition for both well being and the continued availability of resources and Earth system function. Sustainability is further an ambition that has wide appeal, making it one of the first normative concepts of the Anthropocene.

Despite its widespread emergence and adoption, sustainability science continues to suffer from definitional ambiguity within the academe. In Chapter 3, a review of efforts to provide direction and structure to the science reveals a continuum of approaches anchored at either end by differing visions of how the science interfaces with practice (solutions). At one end, basic science of societally defined problems informs decisions about possible solutions and their application. At the other end, applied research directly affects the options available to decision makers. While clear from the literature, survey data further suggests that the dichotomy does not appear to be as apparent in the minds of practitioners.

In Chapter 4, the UHI is first addressed at the synoptic, mesoscale. Urban climate is the most immediate manifestation of the warming global climate for the majority of people on earth. Nearly half of those people live in small to medium sized cities, an understudied scale in urban climate research. Widespread characterization would be useful to decision makers in planning and design. Using a multi-method approach, the mesoscale UHI in the study region is characterized and the secular trend over the last sixty years evaluated. Under isolated ideal conditions the findings indicate a UHI of 5.3 ± 0.97 °C to be present in the study area, the magnitude of which is growing over time.

Although urban heat islands (UHI) are well studied, there remain no panaceas for local scale mitigation and adaptation methods, therefore continued attention to characterization of the phenomenon in urban centers of different scales around the globe is required. In Chapter 5, a local scale analysis of the canopy layer and surface UHI in a medium sized city in North Carolina, USA is conducted using multiple methods including stationary urban sensors, mobile transects and remote sensing. Focusing on the ideal conditions for UHI development during an anticyclonic summer heat event, the study observes a range of UHI intensity depending on the method of observation: 8.7 °C from the stationary urban sensors; 6.9 °C from mobile transects; and, 2.2 °C from remote sensing. Additional attention is paid to the diurnal dynamics of the UHI and its correlation with vegetation indices, dewpoint and albedo. Evapotranspiration is shown to drive dynamics in the study region.

Finally, recognizing that a bridge must be established between the physical science community studying the Urban Heat Island (UHI) effect, and the planning community and decision makers implementing urban form and development policies, Chapter 6 evaluates multiple urban form characterization methods. Methods evaluated include local climate zones (LCZ), national land cover database (NCLD) classes and urban cluster analysis (UCA) to determine their utility in describing the distribution of the UHI based on three standard observation types 1) fixed urban temperature sensors, 2) mobile transects and, 3) remote sensing. Bivariate, regression and ANOVA tests are used to conduct the analyses. Findings indicate that the NLCD classes are best correlated to the UHI intensity and distribution in the study area. Further, while the UCA method is not useful directly, the variables included in the method are predictive based on regression analysis so the potential for better model design exists. Land cover variables including albedo, impervious surface fraction and pervious surface fraction are found to dominate the distribution of the UHI in the study area regardless of observation method.

Chapter 7 provides a summary of findings, and offers a brief analysis of their implications for both the scientific discourse generally, and the study area specifically. In general, the work undertaken does not achieve the full ambition of sustainability science, additional work is required to translate findings to practice and more fully evaluate adoption. The implications for planning and development in the local region are addressed in the context of a major light-rail infrastructure project including several systems level considerations like human health and development. Finally, several avenues for future work are outlined. Within the theoretical development of sustainability science, these pathways include more robust evaluations of the theoretical and actual practice. Within the UHI context, these include development of an integrated urban form characterization model, application of study methodology in other geographic areas and at different scales, and use of novel experimental methods including distributed sensor networks and citizen science.

The Multiscale Systems Immunology project: software for cell-based immunological simulation.

BACKGROUND: Computer simulations are of increasing importance in modeling biological phenomena. Their purpose is to predict behavior and guide future experiments. The aim of this project is to model the early immune response to vaccination by an agent based immune response simulation that incorporates realistic biophysics and intracellular dynamics, and which is sufficiently flexible to accurately model the multi-scale nature and complexity of the immune system, while maintaining the high performance critical to scientific computing. RESULTS: The Multiscale Systems Immunology (MSI) simulation framework is an object-oriented, modular simulation framework written in C++ and Python. The software implements a modular design that allows for flexible configuration of components and initialization of parameters, thus allowing simulations to be run that model processes occurring over different temporal and spatial scales. CONCLUSION: MSI addresses the need for a flexible and high-performing agent based model of the immune system.

Ecological homogenization of urban USA

A visually apparent but scientifically untested outcome of land-use change is homogenization across urban areas, where neighborhoods in different parts of the country have similar patterns of roads, residential lots, commercial areas, and aquatic features. We hypothesize that this homogenization extends to ecological structure and also to ecosystem functions such as carbon dynamics and microclimate, with continental-scale implications. Further, we suggest that understanding urban homogenization will provide the basis for understanding the impacts of urban land-use change from local to continental scales. Here, we show how multi-scale, multidisciplinary datasets from six metropolitan areas that cover the major climatic regions of the US (Phoenix, AZ; Miami, FL; Baltimore, MD; Boston, MA; Minneapolis-St Paul, MN; and Los Angeles, CA) can be used to determine how household and neighborhood characteristics correlate with land-management practices, land-cover composition, and landscape structure and ecosystem functions at local, regional, and continental scales. © The Ecological Society of America.