Molecular classification and prediction of metastatic potential in early malignant melanoma: improvement of prognostic accuracy by quantitative in situ proteomic analysis

The incidence of cutaneous malignant melanoma continues to increase every year, and remains the leading cause of skin cancer death in industrialized countries. In spite of the aggressive nature of advanced melanoma, there are no standard biological assays in clinical usage that can predict metastasis. This may be due, in part, to the inadequacy of reproducible assessment of protein expression using traditional immunohistochemistry. This dissertation will discuss the use of tissue microarrays combined with quantitative in situ molecular analysis of protein expression to allow prediction of melanoma metastasis. Through the identification and validation of novel prognostic biomarkers, we seek to identify subsets of patients that are at high or low risk for melanoma recurrence or melanoma-related death. Some of these biomarkers may also serve as potential targets for future biologic therapy in melanoma, a disease for which no effective medical treatment is currently available. We demonstrate that quantitative assessment of a small number of markers is predictive of metastasis and outcome, augmenting the current system of prognosis.The dissertation begins with a brief introduction on the current state of melanoma diagnosis, staging, and treatment, as well as a review of current efforts to understand the biology of melanoma progression and metastasis. The fundamentals of tissue microarray technology are then described. Critical aspects of quantitative immunohistochemistry, including a description of the Automated Quantitative Analysis (AQUA) system developed in our laboratory, are also addressed. The second chapter demonstrates the use of tissue microarray technology to examine melanoma specimens by the current field standard, with a study of activating transcription factor 2 (ATF2); an example of semi-quantitative immunohistochemical analysis of protein expression. The third chapter provides validation of the AQUA technology on melanoma tissue by evaluation of the human homologue of murine double minute 2 protein (HDM2). Chapter four demonstrates an example of the critical--and beneficial--aspect of subcellular compartmentalization that the AQUA system provides, demonstrating that the ratio of cytoplasmic-to-nuclear expression of activator protein 2 (AP-2) predicts outcome in melanoma patients. The last chapter draws these concepts together and presents results from the analysis of 50 protein biomarkers in melanoma. It also introduces the use of a number of statistical methods (traditional and novel) employed to develop an optimal biomarker set for future analyses

A format for phylogenetic placements

We have developed a unified format for phylogenetic placements, that is, mappings of environmental sequence data (e.g. short reads) into a phylogenetic tree. We are motivated to do so by the growing number of tools for computing and post-processing phylogenetic placements, and the lack of an established standard for storing them. The format is lightweight, versatile, extensible, and is based on the JSON format which can be parsed by most modern programming languages. Our format is already implemented in several tools for computing and post-processing parsimony- and likelihood-based phylogenetic placements, and has worked well in practice. We believe that establishing a standard format for analyzing read placements at this early stage will lead to a more efficient development of powerful and portable post-analysis tools for the growing applications of phylogenetic placement.Comment: Documents version 3 of the forma

On direct measurement of the W production charge asymmetry at the LHC

The prospects for making a direct measurement of the W production charge asymmetry at the LHC are discussed. A modification to the method used at the Tevatron is proposed for measurements at the LHC. The expected sensitivity for such a measurement to parton distribution functions is compared to that for a measurement of the lepton charge asymmetry. The direct measurement approach is found to be less useful for placing constraints on parton distribution functions at the LHC than a measurement of the lepton charge asymmetry.Comment: 18 pages, 10 figures, v2: references and keywords updated v3: Additional paragraph discussing inclusion of W asymmetry in global fits adde

Diversity and Democracy: Agent-Based Modeling in Political Philosophy

Agent-based models have played a prominent role in recent debates about the merits of democracy. In particular, the formal model of Lu Hong and Scott Page and the associated “diversity trumps ability” result has typically been seen to support the epistemic virtues of democracy over epistocracy (i.e., governance by experts). In this paper we first identify the modeling choices embodied in the original formal model and then critique the application of the Hong-Page results to philosophical debates on the relative merits of democracy. In particular we argue that the “best-performing agents” in Hong-Page model should not be interpreted as experts. We next explore a closely related model in which best-performing agents are more plausibly seen as experts and show that the diversity trumps ability result fails to hold. However, with changes in other parameters (such as the deliberation dynamic) the diversity trumps ability result is restored. The sensitivity of this result to parameter choices illustrates the complexity of the link between formal modeling and more general philosophical claims; we use this debate as a platform for a more general discussion of when and how agent-based models can contribute to philosophical discussions

Lead exposure of mainland Australia\u27s top avian predator

Lead (Pb) toxicity, through ingestion of lead ammunition in carcasses, is a threat to scavenging birds worldwide, but has received little attention in Australia. We analyzed lead exposure in the wedge-tailed eagle (Aquila audax), the largest raptor species found in mainland Australia and a facultative scavenger. Eagle carcasses were collected opportunistically throughout south-eastern mainland Australia between 1996 and 2022. Lead concentrations were measured in bone samples from 62 animals via portable X-ray fluorescence (XRF). Lead was detected (concentration \u3e 1 ppm) in 84% (n = 52) of the bone samples. The mean lead concentration of birds in which lead was detected was 9.10 ppm (±SE 1.66). Bone lead concentrations were elevated (10–20 ppm) in 12.9% of samples, and severe ( \u3e 20 ppm) in 4.8% of samples. These proportions are moderately higher than equivalent data for the same species from the island of Tasmania, and are comparable to data from threatened eagle species from other continents. Lead exposure at these levels is likely to have negative impacts on wedge-tailed eagles at the level of the individual and perhaps at a population level. Our results suggest that studies of lead exposure in other Australian avian scavenger species are warranted

A Multidisciplinary Understanding of Polarization

This article aims to describe the last 10 years of the collaborative scientific endeavors on polarization in particular and collective problem-solving in general by our multidisciplinary research team. We describe the team’s disciplinary composition—social psychology, political science, social philosophy/epistemology, and complex systems science— highlighting the shared and unique skill sets of our group members and how each discipline contributes to studying polarization and collective problem-solving. With an eye to the literature on team dynamics, we describe team logistics and processes that we believe make our multidisciplinary team persistent and productive. We emphasize challenges and difficulties caused by disciplinary differences in terms of terminology, units/levels of analysis, methodology, and theoretical assumptions. We then explain how work disambiguating the concepts of polarization and developing an integrative theoretical and methodological framework with complex systems perspectives has helped us overcome these challenges. We summarize the major findings that our research has produced over the past decade, and describe our current research and future directions. Last, we discuss lessons we have learned, including difficulties in a “three models” project and how we addressed them, with suggestions for effective multidisciplinary team research

Wisdom of Crowds, Wisdom of the Few: Expertise versus Diversity across Epistemic Landscapes

In a series of formal studies and less formal applications, Hong and Page offer a ‘diversity trumps ability’ result on the basis of a computational experiment accompanied by a mathematical theorem as explanatory background (Hong & Page 2004, 2009; Page 2007, 2011). “[W]e find that a random collection of agents drawn from a large set of limited-ability agents typically outperforms a collection of the very best agents from that same set” (2004, p. 16386). The result has been extremely influential as an epistemic justification for diversity policy initiatives. Here we show that the ‘diversity trumps ability’ result is tied to the particular random landscape used in Hong and Page’s simulation. We argue against interpreting results on that random landscape in terms of ‘ability’ or ‘expertise.’ These concepts are better modeled on smother and more realistic landscapes, but keeping other parameters the same those are landscapes on which it is groups of the best performing that do better. Smoother landscapes seem to vindicate both the concept and the value of expertise. Change in other parameters, however, also vindicates diversity. With an increase in the pool of available heuristics, diverse groups again do better. Group dynamics makes a difference as well; simultaneous ‘tournament’ deliberation in a group in place of the ‘relay’ deliberation in Hong and Page’s original model further emphasizes an advantage for diversity. ‘Tournament’ 2 dynamics particularly shows the advantage of mixed groups that include both experts and non-experts. As a whole, our modeling results suggest that relative to problem characteristics and conceptual resources, the wisdom of crowds and the wisdom of the few each have a place. We regard ours as a step toward attempting to calibrate their relative virtues in different modelled contexts of intellectual exploration