The historic relationship of species and genes are traditionally depicted using trees. However, not all evolutionary histories are adequately captured by bifurcating processes and an increasing amount of research is devoted towards using networks or network-like structures to capture evolutionary history. Lateral gene transfer (LGT) is a previously controversial mechanism responsible for non tree-like evolutionary histories, and is today accepted as a major force of evolution, particularly in the prokaryotic domain. In this thesis, we present models of gene evolution incorporating both LGTs and duplications, together with efficient computational methods for various inference problems. Specifically, we define a biologically sound combinatorial model for reconciliation of species and gene trees that facilitates simultaneous consideration of duplications and LGTs. We prove that finding most parsimonious reconciliations is NP-hard, but that the problem can be solved efficiently if reconciliations are not required to be acyclic—a condition that is satisfied when analyzing most real-world datasets. We also provide a polynomial-time algorithm for parametric tree reconciliation, a problem analogous to parametric sequence alignment, that enables us to study the entire space of optimal reconciliations under all possible cost schemes. Going beyond combinatorial models, we define the first probabilistic model of gene evolution incorporating a birth-death process generating duplications, LGTs, and losses, together with a relaxed molecular clock model of sequence evolution. Algorithms based on Markov chain Monte Carlo (MCMC) techniques, methods from numerical analysis, and dynamic programming are presented for various probability and parameter inference problems. Finally, we develop methods for analysis of cancer progression, a biological process with many similarities to the process of evolution. Cancer progresses by accumulation of harmful genetic aberrations whose patterns of emergence are graph-like. We develop a model of cancer progression based on trees, and mixtures thereof, that admits an efficient structural EM algorithm for finding Maximum Likelihood (ML) solutions from available cross-sectional data. / QC 20100812

First use and initiation of regular alcohol use has been frequently found to start in adolescence. However, only few studies have also investigated how many adolescents proceed during ages 14–24 to harmful drinking or even develop alcohol use disorders. This paper – using the EDSP baseline sample of 3,021 community respondents from the Munich area – examines the prevalence of use, abuse and dependence and investigates the dose/disorder relationship. Alcohol abuse was reported by 9.7% of respondents and alcohol dependence by 6.2%. Men were more likely to report an alcohol disorder than women, prevalence also increased in the older age cohorts. However, even among 14- to 17-year-olds a substantial proportion of respondents report high and regular consumption rates, the occurrence of abuse and dependence criteria and even a full dependence syndrome. There is however only a moderate association between average number of standard drinks consumed with the risk of developing abuse and dependence. In light of the substantial rates among adolescents and young adults the validity of DSM-IV alcohol disorder criteria is discussed.

Aberrant promoter methylation is known to silence tumor-suppressor genes in prostate cancer. Using a quantitative real-time PCR assay(MethyLight), I determined promoter methylation levels of APC, RASSF1A, CYP26A1 and TBX15 in 219 radical prostatectomies diagnosed between 1998-2001, examined their correlation with clinicopathological follow-up data including Gleason Pattern(GP), Gleason Score(GS) and pathological stage, and explored their potential in predicting biochemical recurrence(BR) using univariate and multivariate analyses. I demonstrated that methylation status of all four genes could accurately differentiate normal from cancerous tissues. Quantitative methylation levels of APC and TBX15 correlated strongly with GP, GS, and pathological stage. Both APC and TBX15 methylation levels could significantly predict BR in univariate analysis(p-value=0.028 and 0.003, respectively). The methylation profiles of APC and TBX15 combined could discriminate patients into high, intermediate, and low risk groups of BR(p-value=0.005). My project demonstrated that quantitative increase in promoter methylation levels of APC and TBX15 were associated with PCa progression.

Aberrant promoter methylation is known to silence tumor-suppressor genes in prostate cancer. Using a quantitative real-time PCR assay(MethyLight), I determined promoter methylation levels of APC, RASSF1A, CYP26A1 and TBX15 in 219 radical prostatectomies diagnosed between 1998-2001, examined their correlation with clinicopathological follow-up data including Gleason Pattern(GP), Gleason Score(GS) and pathological stage, and explored their potential in predicting biochemical recurrence(BR) using univariate and multivariate analyses. I demonstrated that methylation status of all four genes could accurately differentiate normal from cancerous tissues. Quantitative methylation levels of APC and TBX15 correlated strongly with GP, GS, and pathological stage. Both APC and TBX15 methylation levels could significantly predict BR in univariate analysis(p-value=0.028 and 0.003, respectively). The methylation profiles of APC and TBX15 combined could discriminate patients into high, intermediate, and low risk groups of BR(p-value=0.005). My project demonstrated that quantitative increase in promoter methylation levels of APC and TBX15 were associated with PCa progression.

Alkoholkonsum beginnt häufig bereits im Jugendalter. Allerdings fehlen bisher Erkenntnisse darüber, ob, wie häufig und aufgrund welcher Merkmale Jugendlichen und junge Erwachsene auch bereits klinisch definierte Mißbrauchs- und Abhängigkeitsdiagnosen entwickeln. In der vorliegenden Arbeit werden Ergebnisse einer repräsentativen Untersuchung an 3021 Jugendlichen im Alter von 14-24 Jahren vorgestellt. Neben der Prävalenz von Alkoholmißbrauch und -abhängigkeit nach DSM-IV werden Daten zur Häufigkeit und Menge des Alkoholkonsums berichtet sowie erste Symptome beschrieben. 9,7% der befragten Jugendlichen erhielten aufgrund von DSM-IV-Kriterien eine Mißbrauchsdiagnose, 6,2% eine Abhängigkeitsdiagnose. Bei männlichen Jugendlichen war die Prävalenz wesentlich höher als bei weiblichen. Die Prävalenz war in den älteren Geburtskohorten höher. Als erstes Missbrauchssymptom trat am häufigsten "Gebrauch mit körperlicher Gefährdung" (91,9%), als erstes Abhängigkeitssymptom "Toleranzentwicklung" (34,3%) auf. Erste diagnostische Kriterien einer Alkoholstörung traten zumeist deutlich vor dem 18. Lebensjahr auf. Diese Daten unterstreichen, daß Alkoholmißbrauch und -abhängigkeit bereits im Jugend- und frühen Erwachsenenalter häufig sind. / Alcohol use frequently begins in adolescence. However, only few studies have reported the prevalence of alcohol abuse disorders in adolescents. This paper reports results from a representative study in a sample of 3021 adolescents, aged 14-24 years. The Prevalence of alcohol abuse and dependence according to DSM-IV criteria, as well as the prevalence, frequency and quantity of alcohol abuse and a description of the first occuring symptoms, are presented here. Alcohol abuse was reported by 9.7% of respondents and alcohol dependence by 6.2%. Males were more likely to report an alcohol disorder than females, and the prevalence also increased in the older age cohorts. The most frequent initial symptoms were "hazardous use" (91.9%) for abuse and "tolerance" (34.3%) for dependence. First symptoms have been shown to occur long before the age of 18. These results show that even in adolescents and young adults alcohol abuse and dependence are frequent disorders.

This study aims to develop assessment which measures learning progressions for important scientific concepts such as oxidation-reduction (redox) and to identify students¡¦ zone of proximal development (ZPD) through teaching practice incorporating assessment feedback. The assessment items of redox were developed based on the framework of the BEAR (Berkeley Evaluation and Assessment Research) Assessment System. Six experts from chemistry, science education, and educational assessment, and three high school chemistry teachers with fruitful instructional experiences were recruited into the assessment team. Through 24 panel discussions, 28 ordered multiple-choice items were developed. Two samples of Taiwanese middle-school students participated in the test development: one for item revision and the other for validation. Sample 1 and 2 consisted of 626 middle school students (304 8th graders and 322 9th graders) and 903 9th graders, respectively. The materials for instruction integrated assessment feedback were designed by the researcher and two middle-school science teachers through seven group meetings. A teaching experiment was implemented to examine the effect of assessment feedback on students¡¦ understandings of redox and to identify their ZPD. The teaching experiment employed a quasi-experiment with a non-equivalent-group pretest-posttest design. Participants were 196 eighth graders (101 boys and 95 girls) from three middle schools. The findings showed that (a) the BEAR assessment system and Rasch measurement approaches provided a feasible framework for developing validated tools to assess learning progressions; (b) the empirical data supported students¡¦ learning of redox concept usually progressed ¡§from uni-structure to multi-structure¡¨ and ¡§from discrete sub-concepts to integrated concepts¡¨; (c) the teaching practice integrated assessment feedback effectively facilitated students¡¦ understanding of scientific concepts; (d) the assessment of learning progressions provided a mechanism for identifying students¡¦ ZPD and helped realize the abtract idea of ZPD in teaching practices. The main contributions of the study included (a) demostrating how to carry out the idea of ZPD into teaching practices through linking learning progressions and ZPD; (b) presenting how to apply BEAR assessment system and Rasch techniques to develop tools for assessing learning progressions; (c) developing a set of items for assessing learning progressions of redox and a series of materials for teaching practices integrated assessment feedback.

Thesis--University of Oklahoma. / Includes bibliographical references (leaves 39-41).

The literacy skills of students have become a significant concern among legislators and educators. The federal government has responded to this by enacting legislation that increases state accountability to provide evidence-based interventions to struggling readers. In response, the State of Florida has mandated mandatory retention for third-grade students who are at risk for reading failure. Third-grade students who do not pass the Florida comprehensive Assessment Test-Reading (FCAT) are retained. Students who score at Level 1 are retained, and students who scored at Levels 2 through 5 are promoted. Research has indicated that retention has been an ineffective intervention to improve academic performance. However, it is difficult to compare research findings with Florida’s current retention plan. Previous research has not delineated the intervention strategies that were utilized during the retention year. Florida requires that all students are provided evidence-based reading remediation. The purpose of this study was to explore the association of Florida’s model of student progression and academic achievement. More specifically, the study investigated the academic outcomes of third-grade students who scored within 10 scaled score points below the student progression achievement cut-off, attained a Level 1 designation in 2003 and were retained, and students who scored within 10 scaled score points above the student progression achievement cut-off, attained a Level 2 designation in 2003 and were promoted to fourth grade. Results indicated that 87% of the higher performing retained students subsequently scored at Level 2 or higher in 2004 while 67% of the promoted, low achieving student scored at Level 2 or higher in 2004. Furthermore, gender, SES and race were significantly associated with the reading outcomes of higher achieving retained and promoted, low achieving students. This study contributes to the literature by examining the outcomes of a retention model within a framework of academic remediation. In addition, the utility of high stakes testing and retention decisions were also examined. Future implications for research include direct comparisons of retained and promoted students, a longitudinal research design to examine the long-term effects of retention, and the identification of more effective services and intervention strategies to target at-risk students.

Estimating the quantity of water that reaches the water table following an infiltration event is vital for modeling and management of water resources. Estimating the time scale of groundwater recharge after a rainfall event is difficult because of the dependence on nonlinear soil characteristics and variability in antecedent conditions. Modeling the flow of water through the variably saturated zone is computationally intensive since it requires simulation of Richards' equation, a nonlinear partial differential equation without a closed-form analytical solution, with parametric relationships that are difficult to approximate. Hence, regional scale coupled (surface water - groundwater) hydrological models make simplistic assumptions about the quantity and timing of recharge following infiltration. For simplicity, such models assume the quantity of recharge to be a fraction of the total rainfall and the time to recharge the saturated groundwater is scaled proportionally to the depth to water table, in lieu of simulating computationally intensive flow in the variably saturated zone. In integrated or coupled (surface water - groundwater) regional scale hydrological models, better representation of the timing and quantity of groundwater recharge is required and important for water resources management. This dissertation presents a practical groundwater recharge estimation method and relationships that predict the timing and volume accumulation of groundwater recharge to moderate to deep water table settings. This study combines theoretical, empirical, and simulation techniques to develop a relatively simple model to estimate the propagation of the soil moisture wetting front through variably saturated soil. This model estimates the time scale and progression of recharge following infiltration for a specified depth to water table, saturated hydraulic conductivity and equilibrium moisture condition. High-resolution soil moisture data from a set of experiments conducted in a laboratory soil column were used to calibrate the HYDRUS-1D model. The calibrated model was used to analyze the time scale of recharge by varying soil hydraulic properties and simulating the application of rainfall pulses of varying volume and intensities. Modeling results were used to develop an equation that relates the non-dimensional travel time of the wetting front to excess moisture moisture content above equilibrium. This research indicates that for a soil with a known retention curve, the wetting front arrival time at a given depth can be described by a power law, where the power is a function of the saturated hydraulic conductivity. This equation relates the non-dimensional travel time of the wetting front to excess moisture content above the equilibrium moisture content. Since the equilibrium moisture content is dependent on the water retention curve, the powers in the equation governing the timing of recharge depend on the saturated hydraulic conductivity for a large variation in water retention curve. Also, the power law relates recharge (normalized by applied pulse volume) to time (normalized by the time of arrival of wetting front at that depth). The resulting equations predicted the model simulated normalized (relative) recharge with root mean square errors of less than 14 percent for the tested cases.

Οι ανθρώπινοι όγκοι συνοδεύονται από κάποιου βαθμού φλεγμονή. Οι παράγοντες του καρκινικού κυττάρου που προκαλούν και ρυθμίζουν τη φλεγμονή, καθώς και οι επιδράσεις της φλεγμονής αυτής πάνω στον ίδιο τον όγκο αποτελούν σημαντικά ερευνητικά ζητούμενα. Τρέχοντα δεδομένα υποστηρίζουν ότι συγκεκριμένες γενετικές βλάβες του καρκινικού κυττάρου αποτελούν σημαντικούς τελεστές της παρανεοπλασματικής φλεγμονής. Συγκεκριμένα, μεταλλάξεις του ογκογονιδίου Kras, συχνές σε καρκίνους των πνευμόνων, του παγκρέατος και του εντέρου πιθανά συντελούν στη δημιουργία ενός φλεγμονώδους-ογκοπροαγωγού μικροπεριβάλλοντος. Στόχος της παρούσας εργασίας ήταν η μελέτη του ρόλου των μεταλλάξεων Kras στη νεοπλασματική πρόοδο και την παρανεοπλασματική φλεγμονή. Για το σκοπό αυτό, πραγματοποιήθηκε γονοτύπηση καρκινικών σειρών ποντικού για μεταλλάξεις Kras. Σε κυτταρική σειρά που φέρει ενεργοποιητική μετάλλαξη Kras αποσιωπήθηκε σταθερά η έκφραση του με shRNA. Η μητρική και η θυγατρική σειρές εμφυτεύθηκαν στο υποδόριο και τον υπεζωκότα ανοσοεπαρκών ποντικών. Η αποσιώπηση του Kras οδήγησε σε μικρότερου βαθμού φλεγμονή και νεοπλασματική αύξηση, σε σύγκριση με τους μητρικούς όγκους. Ο κύριος πληθυσμός ανοσολογικών κυττάρων στους όγκους ήταν CD45+CD11b+ μυελοκύτταρα, τα οποία πρόσφατα βρέθηκε πως ρυθμίζονται φαινοτυπικά στο σπλήνα. Η σπληνεκτομή δεν επηρέασε την ανάπτυξη υποδόριων όγκων και νεοπλασματικής φλεγμονής από μητρικά και shKras κύτταρα. Αντίθετα, η σπληνεκτομή είχε ευεργετικά αποτελέσματα σε ζωϊκό πρότυπο κακοήθους υπεζωκοτικής συλλογής οδηγώντας σε ελάττωση συσσώρευσης υγρού και φλεγμονωδών κυττάρων. Συμπερασματικά, οι μεταλλάξεις Kras φαίνεται να παίζουν ρόλο στη νεοπλασματική πρόοδο και τη σχετιζόμενη φλεγμονή, αλληλεπιδρώντας με κάποιο σπληνοεξαρτώμενο πληθυσμό μυελοκυττάρων. Οι δράσεις αυτού του κυτταρικού πληθυσμού εξαρτώνται από το νεοπλασματικό μικροπεριβάλλον. / The human tumors are accompanied with some kind of inflammation. The factors of the cancer cell that cause and regulate this inflammation, as well as the influence of this inflammation on the tumor itself constitute an important research aim. Current data argue that specific genetic damage of the cancer cell constitute important operands of the paraneoplastic inflammation. In particular, mutations of the oncogene Kras, common in cancers of the lungs, the pancreas and the colon, possibly contribute to the initiation of a an inflammatory-tumorpromoting microenvironment. The aim of the current thesis was the study of the role of the Kras mutations in the neoplastic progression and the paraneoplastic inflammation. For this purpose, genotyping of murine cancer cell lines for Kras mutations was performed. In cancer cell line with activating Kras mutation, the expression of the Kras was silenced through shRNA. Both the parental and the daughter cell lines were implanted both subcutaneously and in the pleural cavity of immunocompetent mice. The silencing of the Kras led to a lower rate of inflammation and neoplastic growth, in comparison with the parental tumors. The main immunological population in the tumors was CD45+CD11b+ myeloid derived cells which were recently found to be phenotypically regulated in the spleen. The splenectomy did not influence the growth of subcutaneous tumors or neoplastic inflammation from parental and shKras cells. In contrast, the splenectomy had positive results on animal model of malignant pleural effusion, leading to lower collection of liquid and inflammatory cells. In conclusion, the mutations of Kras are shown to play a role in the neoplastic progression and the associated inflammation, interacting with a spleen- dependent population of myeloid derived cells. The actions of this cell population depend on the neoplastic microenvironment.