Phylogenetic analysis of within -host serially-sampled viral data

The primary goal of this dissertation is the study of patterns of viral evolution inferred from serially-sampled sequence data, i.e., sequence data obtained from strains isolated at consecutive time points from a single patient or host. RNA viral populations have an extremely high genetic variability, largely due to their astronomical population sizes within host systems, high replication rate, and short generation time. It is this aspect of their evolution that demands special attention and a different approach when studying the evolutionary relationships of serially-sampled sequence data. New methods that analyze serially-sampled data were developed shortly after a groundbreaking HIV-1 study of several patients from which viruses were isolated at recurring intervals over a period of 10 or more years. These methods assume a tree-like evolutionary model, while many RNA viruses have the capacity to exchange genetic material with one another using a process called recombination. ^ A genealogy involving recombination is best described by a network structure. A more general approach was implemented in a new computational tool, Sliding MinPD, one that is mindful of the sampling times of the input sequences and that reconstructs the viral evolutionary relationships in the form of a network structure with implicit representations of recombination events. The underlying network organization reveals unique patterns of viral evolution and could help explain the emergence of disease-associated mutants and drug-resistant strains, with implications for patient prognosis and treatment strategies. In order to comprehensively test the developed methods and to carry out comparison studies with other methods, synthetic data sets are critical. Therefore, appropriate sequence generators were also developed to simulate the evolution of serially-sampled recombinant viruses, new and more through evaluation criteria for recombination detection methods were established, and three major comparison studies were performed. The newly developed tools were also applied to "real" HIV-1 sequence data and it was shown that the results represented within an evolutionary network structure can be interpreted in biologically meaningful ways. ^

Serial evolutionary networks of within-patient HIV-1 sequences reveal patterns of evolution of X4 strains

Background The HIV virus is known for its ability to exploit numerous genetic and evolutionary mechanisms to ensure its proliferation, among them, high replication, mutation and recombination rates. Sliding MinPD, a recently introduced computational method [1], was used to investigate the patterns of evolution of serially-sampled HIV-1 sequence data from eight patients with a special focus on the emergence of X4 strains. Unlike other phylogenetic methods, Sliding MinPD combines distance-based inference with a nonparametric bootstrap procedure and automated recombination detection to reconstruct the evolutionary history of longitudinal sequence data. We present serial evolutionary networks as a longitudinal representation of the mutational pathways of a viral population in a within-host environment. The longitudinal representation of the evolutionary networks was complemented with charts of clinical markers to facilitate correlation analysis between pertinent clinical information and the evolutionary relationships. Results Analysis based on the predicted networks suggests the following:: significantly stronger recombination signals (p = 0.003) for the inferred ancestors of the X4 strains, recombination events between different lineages and recombination events between putative reservoir virus and those from a later population, an early star-like topology observed for four of the patients who died of AIDS. A significantly higher number of recombinants were predicted at sampling points that corresponded to peaks in the viral load levels (p = 0.0042). Conclusion Our results indicate that serial evolutionary networks of HIV sequences enable systematic statistical analysis of the implicit relations embedded in the topology of the structure and can greatly facilitate identification of patterns of evolution that can lead to specific hypotheses and new insights. The conclusions of applying our method to empirical HIV data support the conventional wisdom of the new generation HIV treatments, that in order to keep the virus in check, viral loads need to be suppressed to almost undetectable levels.

A fresh look at decision making in international investment choices: Firm international coherence and home-host country relatedness

Understanding how decisions for international investments are made and how this affects the overall pattern of investments and firm’s performance is of particular importance both in strategy and international business research. This dissertation introduced first home-host country relatedness (HHCR) as the degree to which countries are efficiently combined within the investment portfolios of firms. It theorized and demonstrated that HHCR will vary with the motivation for investments along at least two key dimensions: the nature of foreign investments and the connectedness of potential host countries to the rest of the world. Drawing on cognitive psychology and decision-making research, it developed a theory of strategic decision making proposing that strategic solutions are chosen close to a convenient anchor. Building on research on memory imprinting, it also proposed that managers tend to rely on older knowledge representation. In the context of international investment decisions, managers use their home countries as an anchor and are more likely to choose as a site for foreign investments host countries that are ‘close’ to the home country. These decisions are also likely to rely more strongly on closeness to time invariant country factors of historic and geographic nature rather than time-variant institutions. Empirical tests using comprehensive investments data by all public multinational companies (MNC) worldwide, or over 15,000 MNCs with over half a million subsidiaries, support the claims. Finally, the dissertation introduced the concept of International Coherence (IC) defined as the degree to which an MNE’s network comprises countries that are related. It was hypothesized that maintaining a high level of coherence is important for firm performance and will enhance it. Also, the presence of international coherence mitigates some of the negative effects of unrelated product diversification. Empirical tests using data on foreign investments of over 20,000 public firms, while also developing a home-host country relatedness index for up to 24,300 home-host pairs, provided support for the theory advanced.

Current Status of Collectibility of Gaming-Related Credit Dollars

In her piece entitled - Current Status Of Collectability Of Gaming-Related Credit Dollars - Ruth Lisa Wenof, Graduate Student at Florida International University initially states: “Credit is an important part of incentives used to lure gamblers to gaming establishments. However, a collection problem exists in casinos retrieving gaming-related credit losses of individuals living in states where gambling is illegal. The author discusses the history of this question, citing recent cases related to Atlantic City.” This author’s article is substantially laden with legal cases associated with casinos in New Jersey; Atlantic City to be exact. The piece is specific to the segment of the gaming industry that the title suggests, and as such is written in a decidedly technical style. “Legalized casino gaming, which was approved by the citizens of New Jersey on November 8, 1976, has been used as a unique tool of urban redevelopment for Atlantic City,” Wenof says in providing some background on this ‘Jersey shore municipality. “Since Resorts International opened its casino…revenues from gambling have increased rapidly. Resorts' gross win in 1978 was $134 million,” Wenof says. “Since then, the combined gross win of the city's 11 casinos has been just shy of $7.5 billion.” The author points out that the competition for casino business is fierce and that credit dollars play an integral role in soliciting such business. “Credit plays a most important part in every casino hotel. This type of gambler is given every incentive to come to a particular hotel,” says the author. “Airplanes, limousines, suites, free meals, and beverages all become a package for the person who can sign a marker. The credit department of a casino is similar to that of a bank. A banker who loans money knows that it must be paid back or his bank will fail. This is indeed true of a casino,” Wenof warns in outlining the potential problem that this article is fundamentally designed around. In providing further background on credit essentials and possible pitfalls, Wenof affords: “…on the Casino Control Act the State Commission of Investigation recommended to the legislature that casinos should not be allowed to extend credit at all, by reason of a concern for illicit diversion of revenues, which is popularly called skimming within the industry…” Although skimming is an after-the-fact problem, and is parenthetic to loan returns, it is an important element of the collective [sic] credit scheme. “A collection problem of prime importance is if a casino can get back gaming-related credit dollars advanced by the casino to a gambler who lives in a state where gambling is illegal,” is a central factor to consider, Wenof reveals. This is a primary focus of this article. Wenof touches on the social/societal implications of gambling, and then continues the discussion by citing a host of legal cases pertaining to debt collection.

Relative roles of dispersal dynamics and competition in determining the isotopic niche breadth of a wetland fish

1. The niche variation hypothesis predicts that among-individual variation in niche use will increase in the presence of intraspecific competition and decrease in the presence of interspecific competition. We sought to determine whether the local isotopic niche breadth of fish inhabiting a wetland was best explained by competition for resources and the niche variation hypothesis, by dispersal of individuals from locations with different prey resources or by a combination of the two. We analysed stable isotopes of carbon and nitrogen as indices of feeding niche and compared metrics of within-site spread to characterise site-level isotopic niche breadth. We then evaluated the explanatory power of competing models of the direct and indirect effects of several environmental variables spanning gradients of disturbance, competition strength and food availability on among-individual variation of the eastern mosquitofish (Gambusia holbrooki). 2. The Dispersal model posits that only the direct effect of disturbance (i.e. changes in water level known to induce fish movement) influences among-individual variation in isotopic niche. The Partitioning model allows for only direct effects of local food availability on among-individual variation. The Combined model allows for both hypotheses by including the direct effects of disturbance and food availability. 3. A linear regression of the Combined model described more variance than models limited to the variables of either the Dispersal or Partitioning models. Of the independent variables considered, the food availability variable (per cent edible periphyton) explained the most variation in isotopic niche breadth, followed closely by the disturbance variable (days since last drying event). 4. Structural equation modelling provided further evidence that the Combined model was best supported by the data, with the Partitioning and the Dispersal models only modestly less informative. Again, the per cent edible periphyton was the variable with the largest direct effect on niche variability, with other food availability variables and the disturbance variable only slightly less important. Indirect effects of heterospecific and conspecific competitor densities were also important, through their effects on prey density. 5. Our results support the Combined hypotheses, although partitioning mechanisms appear to explain the most diet variation among individuals in the eastern mosquitofish. The results also support some predictions of the niche variation hypothesis, although both conspecific and interspecific competition appeared to increase isotopic niche breadth in contrast to predictions that interspecific competition would decrease it. We think this resulted from high diet overlap of co-occurring species, most of which consume similar macroinvertebrates.

PROTEOMIC ANALYSIS OF WOLBACHIA SYMBIOSIS WITHIN THE DROSOPHILA OVARY

Wolbachia pipientis are bacterial endosymbionts carried by millions of invertebrate species, including ~40% of insect species and some filarial nematodes. In insects, basic Wolbachia research has potential applications in controlling vector borne disease. Conversely, Wolbachia of filarial nematodes are causative agents of neglected tropical diseases such as lymphatic filariasis and African river blindness. However, remarkably little is known about how Wolbachia interact with their hosts at the molecular level. Understanding this is important to inform the basis for symbiosis and help prevent human disease. I used a high-throughput proteomics approach to study how Drosophila host cells are modified by Wolbachia infection. This analysis identified 23 Drosophila proteins that significantly changed in amount as a result of Wolbachia infection. A subset of differentially abundant host proteins were consistent with Wolbachia-associated phenotypes reported previously. This study also provides the first ever discovery-based evidence for a Wolbachia-associated change in maternal germline histone loads, which has possible implications in Rescue of a common Wolbachia-induced reproductive manipulation known as Cytoplasmic Incompatibility.