Chlorine contribution to quantitative structure and activity relationship models of disinfection by -products' quantum chemical descriptors and toxicities

Quantitative Structure-Activity Relationship (QSAR) has been applied extensively in predicting toxicity of Disinfection By-Products (DBPs) in drinking water. Among many toxicological properties, acute and chronic toxicities of DBPs have been widely used in health risk assessment of DBPs. These toxicities are correlated with molecular properties, which are usually correlated with molecular descriptors. The primary goals of this thesis are: (1) to investigate the effects of molecular descriptors (e.g., chlorine number) on molecular properties such as energy of the lowest unoccupied molecular orbital (E LUMO) via QSAR modelling and analysis; (2) to validate the models by using internal and external cross-validation techniques; (3) to quantify the model uncertainties through Taylor and Monte Carlo Simulation. One of the very important ways to predict molecular properties such as ELUMO is using QSAR analysis. In this study, number of chlorine (NCl ) and number of carbon (NC) as well as energy of the highest occupied molecular orbital (EHOMO) are used as molecular descriptors. There are typically three approaches used in QSAR model development: (1) Linear or Multi-linear Regression (MLR); (2) Partial Least Squares (PLS); and (3) Principle Component Regression (PCR). In QSAR analysis, a very critical step is model validation after QSAR models are established and before applying them to toxicity prediction. The DBPs to be studied include five chemical classes: chlorinated alkanes, alkenes, and aromatics. In addition, validated QSARs are developed to describe the toxicity of selected groups (i.e., chloro-alkane and aromatic compounds with a nitro- or cyano group) of DBP chemicals to three types of organisms (e.g., Fish, T. pyriformis, and P.pyosphoreum) based on experimental toxicity data from the literature. The results show that: (1) QSAR models to predict molecular property built by MLR, PLS or PCR can be used either to select valid data points or to eliminate outliers; (2) The Leave-One-Out Cross-Validation procedure by itself is not enough to give a reliable representation of the predictive ability of the QSAR models, however, Leave-Many-Out/K-fold cross-validation and external validation can be applied together to achieve more reliable results; (3) E LUMO are shown to correlate highly with the NCl for several classes of DBPs; and (4) According to uncertainty analysis using Taylor method, the uncertainty of QSAR models is contributed mostly from NCl for all DBP classes.

Chlorine Contribution to Quantitative Structure and Activity Relationship Models of Disinfection By-Products' Quantum Chemical Descriptors and Toxicities

Quantitative Structure-Activity Relationship (QSAR) has been applied extensively in predicting toxicity of Disinfection By-Products (DBPs) in drinking water. Among many toxicological properties, acute and chronic toxicities of DBPs have been widely used in health risk assessment of DBPs. These toxicities are correlated with molecular properties, which are usually correlated with molecular descriptors. The primary goals of this thesis are: 1) to investigate the effects of molecular descriptors (e.g., chlorine number) on molecular properties such as energy of the lowest unoccupied molecular orbital (ELUMO) via QSAR modelling and analysis; 2) to validate the models by using internal and external cross-validation techniques; 3) to quantify the model uncertainties through Taylor and Monte Carlo Simulation. One of the very important ways to predict molecular properties such as ELUMO is using QSAR analysis. In this study, number of chlorine (NCl) and number of carbon (NC) as well as energy of the highest occupied molecular orbital (EHOMO) are used as molecular descriptors. There are typically three approaches used in QSAR model development: 1) Linear or Multi-linear Regression (MLR); 2) Partial Least Squares (PLS); and 3) Principle Component Regression (PCR). In QSAR analysis, a very critical step is model validation after QSAR models are established and before applying them to toxicity prediction. The DBPs to be studied include five chemical classes: chlorinated alkanes, alkenes, and aromatics. In addition, validated QSARs are developed to describe the toxicity of selected groups (i.e., chloro-alkane and aromatic compounds with a nitro- or cyano group) of DBP chemicals to three types of organisms (e.g., Fish, T. pyriformis, and P.pyosphoreum) based on experimental toxicity data from the literature. The results show that: 1) QSAR models to predict molecular property built by MLR, PLS or PCR can be used either to select valid data points or to eliminate outliers; 2) The Leave-One-Out Cross-Validation procedure by itself is not enough to give a reliable representation of the predictive ability of the QSAR models, however, Leave-Many-Out/K-fold cross-validation and external validation can be applied together to achieve more reliable results; 3) ELUMO are shown to correlate highly with the NCl for several classes of DBPs; and 4) According to uncertainty analysis using Taylor method, the uncertainty of QSAR models is contributed mostly from NCl for all DBP classes.

The dynamics of movement: Toward a definition of a Latin American identity in contemporary fiction

Concha Meléndez opened up a venue for the discussion of a Latin American identity in works of literature when she implied that the great Latin American novel would gestate in the cities, the space where the typical Latin American would achieve an ideal state of consciousness and intellectual capabilities. ^ Her point of view mirrored nineteenth-century debate on a Latin American identity. Similar to her viewpoint, intellectuals of this period viewed the cities and their inhabitants of European extraction, as the ideal spaces and people on which an identity could be defined. However, the present state of urban and rural areas in Latin America demonstrates that there is no such clear-cut division of city and countryside or of their inhabitants. The dynamics of movement, from rural to urban areas, of people of diverse ethnic, and socioeconomic backgrounds, make it difficult to uphold descriptors of space, race, or culture, as sole descriptors of an identity. ^ A study of five twentieth-century novels from North and South America, La muerte de Artemio Cruz (1962), Hasta no verte Jesús mío (1969), Los ríos profundos (1981), La casa de los espíritus (1982), and Los años con Laura Díaz (1999) reveal that the dynamism of movement, between countryside, and cities of peoples of distinct races and social backgrounds, hamper the definition of a collective identity in specific spaces. As characters move, they are constantly reconfiguring their identities and creating tensions and conflicts that intensify social, racial and economic divisions in society. This makes it difficult to ascribe permanent identity descriptors, much less define a collective identity. ^ However, as writers of fiction address the malaise in Latin American societies, they have unearthed descriptors such as history, economy, land, and movement that advance a collective definition of self in these societies. Additionally, female characters have been granted a new identity. The overwhelming evidence in this study points to ‘land’ as the prime factor in the identity dilemma and suggests that a definition will not be possible until the vast landless populace is granted a space they can call home. Only then, perhaps, will Meléndez novel surface. ^

Knowledge assisted data management and retrieval in multimedia database systems

With the proliferation of multimedia data and ever-growing requests for multimedia applications, there is an increasing need for efficient and effective indexing, storage and retrieval of multimedia data, such as graphics, images, animation, video, audio and text. Due to the special characteristics of the multimedia data, the Multimedia Database management Systems (MMDBMSs) have emerged and attracted great research attention in recent years. Though much research effort has been devoted to this area, it is still far from maturity and there exist many open issues. In this dissertation, with the focus of addressing three of the essential challenges in developing the MMDBMS, namely, semantic gap, perception subjectivity and data organization, a systematic and integrated framework is proposed with video database and image database serving as the testbed. In particular, the framework addresses these challenges separately yet coherently from three main aspects of a MMDBMS: multimedia data representation, indexing and retrieval. In terms of multimedia data representation, the key to address the semantic gap issue is to intelligently and automatically model the mid-level representation and/or semi-semantic descriptors besides the extraction of the low-level media features. The data organization challenge is mainly addressed by the aspect of media indexing where various levels of indexing are required to support the diverse query requirements. In particular, the focus of this study is to facilitate the high-level video indexing by proposing a multimodal event mining framework associated with temporal knowledge discovery approaches. With respect to the perception subjectivity issue, advanced techniques are proposed to support users' interaction and to effectively model users' perception from the feedback at both the image-level and object-level.

Climatic Controls on Phytoplankton Biomass in a Sub-tropical Estuary, Florida Bay, USA

The extraction of climatic signals from time series of biogeochemical data is further complicated in estuarine regions because of the dynamic interaction of land, ocean, and atmosphere. We explored the behavior of potential global and regional climatic stressors to isolate specific shifts or trends, which could have a forcing role on the behavior of biogeochemical descriptors of water quality and phytoplankton biomass from Florida Bay, as an example of a sub-tropical estuary. We performed statistical analysis and subdivided the bay into six zones having unique biogeochemical characteristics. Significant shifts in the drivers were identified in all the chlorophyll a time series. Chlorophyll a concentrations closely follow global forcing and display a generalized declining trend on which seasonal oscillations are superimposed, and it is only interrupted by events of sudden increase triggered by storms which are followed by a relatively rapid return to pre-event conditions trailing again the long-term trend.

Periphyton light transmission relationships in Florida Bay and the Florida Keys, USA

Light transmission was measured through intact, submerged periphyton communities on artificial seagrass leaves. The periphyton communities were representative of the communities on Thalassia testudinum in subtropical seagrass meadows. The periphyton communities sampled were adhered carbonate sediment, coralline algae, and mixed algal assemblages. Crustose or film-forming periphyton assemblages were best prepared for light transmission measurements using artificial leaves fouled on both sides, while measurements through three-dimensional filamentous algae required the periphyton to be removed from one side. For one-sided samples, light transmission could be measured as the difference between fouled and reference artificial leaf samples. For two-sided samples, the percent periphyton light transmission to the leaf surface was calculated as the square root of the fraction of incident light. Linear, exponential, and hyperbolic equations were evaluated as descriptors of the periphyton dry weight versus light transmission relationship. Hyperbolic and exponential decay models were superior to linear models and exhibited the best fits for the observed relationships. Differences between the coefficients of determination (r2) of hyperbolic and exponential decay models were statistically insignificant. Constraining these models for 100% light transmission at zero periphyton load did not result in any statistically significant loss in the explanatory capability of the models. In most all cases, increasing model complexity using three-parameter models rather than two-parameter models did not significantly increase the amount of variation explained. Constrained two-parameter hyperbolic or exponential decay models were judged best for describing the periphyton dry weight versus light transmission relationship. On T. testudinum in Florida Bay and the Florida Keys, significant differences were not observed in the light transmission characteristics of the varying periphyton communities at different study sites. Using pooled data from the study sites, the hyperbolic decay coefficient for periphyton light transmission was estimated to be 4.36 mg dry wt. cm−2. For exponential models, the exponential decay coefficient was estimated to be 0.16 cm2 mg dry wt.−1.

Covalent protein adduction by drugs of abuse

Recreational abuse of the drugs cocaine, methamphetamine, and morphine continues to be prevalent in the United States of America and around the world. While numerous methods of detection exist for each drug, they are generally limited by the lifetime of the parent drug and its metabolites in the body. However, the covalent modification of endogenous proteins by these drugs of abuse may act as biomarkers of exposure and allow for extension of detection windows for these drugs beyond the lifetime of parent molecules or metabolites in the free fraction. Additionally, existence of covalently bound molecules arising from drug ingestion can offer insight into downstream toxicities associated with each of these drugs. This research investigated the metabolism of cocaine, methamphetamine, and morphine in common in vitro assay systems, specifically focusing on the generation of reactive intermediates and metabolites that have the potential to form covalent protein adducts. Results demonstrated the formation of covalent adduction products between biological cysteine thiols and reactive moieties on cocaine and morphine metabolites. Rigorous mass spectrometric analysis in conjunction with in vitro metabolic activation, pharmacogenetic reaction phenotyping, and computational modeling were utilized to characterize structures and mechanisms of formation for each resultant thiol adduction product. For cocaine, data collected demonstrated the formation of adduction products from a reactive arene epoxide intermediate, designating a novel metabolic pathway for cocaine. In the case of morphine, data expanded on known adduct-forming pathways using sensitive and selective analysis techniques, following the known reactive metabolite, morphinone, and a proposed novel metabolite, morphine quinone methide. Data collected in this study describe novel metabolic events for multiple important drugs of abuse, culminating in detection methods and mechanistic descriptors useful to both medical and forensic investigators when examining the toxicology associated with cocaine, methamphetamine, and morphine.

A meta -analysis of empirical research studies on resilience among students at -risk for school failure

Being at-risk is a growing problem in the U.S. because of disturbing societal trends such as unemployment, divorce, substance abuse, child abuse and neglect, and the new threat of terrorist violence. Resilience characterizes individuals who rebound from or adapt to adversities such as these, and academic resilience distinguishes at-risk students who succeed in school despite hardships. ^ The purpose of this research was to perform a meta-analysis to examine the power of resilience and to suggest ways educators might improve academic resilience, which was operationalized by satisfactory test scores and grades. In order to find all studies that were relevant to academic resilience in at-risk kindergarten through 12th-grade students, extensive electronic and hardcopy searches were conducted, and these resulted in a database of 421 articles. Two hundred eighty seven of these were rejected quickly, because they were not empirical research. Upon further examination, another 106 were rejected for not meeting study protocol criteria. Ultimately, 28 studies were coded for study level descriptors and effect size variables. ^ Protective factors for resilience were found to originate in physical, psychological, and behavioral domains on proximal/intraindividual, transitional/intrafamilial, or distal/extrafamilial levels. Effect sizes (ESs) for these were weighted and the means for each level or category were interpreted by commonly accepted benchmarks. Mean effect sizes for proximal (M = .27) and for transitional (M = .15) were small but significant. The mean effect size for the distal level was insignificant. This supported the hypotheses that the proximal level was the source of most protective factors for academic resilience in at-risk students followed by the transitional level. The distal effect size warranted further research particularly in light of the small number of studies (n = 11) contributing effect sizes to that category. A homogeneity test indicated a search for moderators, i.e., study variables affecting outcomes, was justified. “Category” was the largest moderator. Graphs of weighted mean effect sizes in the physical, psychological, and behavioral domains were plotted for each level to better illustrate the findings of the meta-analysis. Suggestions were made for combining resilience development with aspects of positive psychology to promote resilience in the schools. ^

Development, validation and uncertainty analysis of quantitative structure and activity relationship models for Log P of disinfection by -products

Hydrophobicity as measured by Log P is an important molecular property related to toxicity and carcinogenicity. With increasing public health concerns for the effects of Disinfection By-Products (DBPs), there are considerable benefits in developing Quantitative Structure and Activity Relationship (QSAR) models capable of accurately predicting Log P. In this research, Log P values of 173 DBP compounds in 6 functional classes were used to develop QSAR models, by applying 3 molecular descriptors, namely, Energy of the Lowest Unoccupied Molecular Orbital (ELUMO), Number of Chlorine (NCl) and Number of Carbon (NC) by Multiple Linear Regression (MLR) analysis. The QSAR models developed were validated based on the Organization for Economic Co-operation and Development (OECD) principles. The model Applicability Domain (AD) and mechanistic interpretation were explored. Considering the very complex nature of DBPs, the established QSAR models performed very well with respect to goodness-of-fit, robustness and predictability. The predicted values of Log P of DBPs by the QSAR models were found to be significant with a correlation coefficient R2 from 81% to 98%. The Leverage Approach by Williams Plot was applied to detect and remove outliers, consequently increasing R 2 by approximately 2% to 13% for different DBP classes. The developed QSAR models were statistically validated for their predictive power by the Leave-One-Out (LOO) and Leave-Many-Out (LMO) cross validation methods. Finally, Monte Carlo simulation was used to assess the variations and inherent uncertainties in the QSAR models of Log P and determine the most influential parameters in connection with Log P prediction. The developed QSAR models in this dissertation will have a broad applicability domain because the research data set covered six out of eight common DBP classes, including halogenated alkane, halogenated alkene, halogenated aromatic, halogenated aldehyde, halogenated ketone, and halogenated carboxylic acid, which have been brought to the attention of regulatory agencies in recent years. Furthermore, the QSAR models are suitable to be used for prediction of similar DBP compounds within the same applicability domain. The selection and integration of various methodologies developed in this research may also benefit future research in similar fields.

Covalent Protein Adduction by Drugs of Abuse

Recreational abuse of the drugs cocaine, methamphetamine, and morphine continues to be prevalent in the United States of America and around the world. While numerous methods of detection exist for each drug, they are generally limited by the lifetime of the parent drug and its metabolites in the body. However, the covalent modification of endogenous proteins by these drugs of abuse may act as biomarkers of exposure and allow for extension of detection windows for these drugs beyond the lifetime of parent molecules or metabolites in the free fraction. Additionally, existence of covalently bound molecules arising from drug ingestion can offer insight into downstream toxicities associated with each of these drugs. This research investigated the metabolism of cocaine, methamphetamine, and morphine in common in vitro assay systems, specifically focusing on the generation of reactive intermediates and metabolites that have the potential to form covalent protein adducts. Results demonstrated the formation of covalent adduction products between biological cysteine thiols and reactive moieties on cocaine and morphine metabolites. Rigorous mass spectrometric analysis in conjunction with in vitro metabolic activation, pharmacogenetic reaction phenotyping, and computational modeling were utilized to characterize structures and mechanisms of formation for each resultant thiol adduction product. For cocaine, data collected demonstrated the formation of adduction products from a reactive arene epoxide intermediate, designating a novel metabolic pathway for cocaine. In the case of morphine, data expanded on known adduct-forming pathways using sensitive and selective analysis techniques, following the known reactive metabolite, morphinone, and a proposed novel metabolite, morphine quinone methide. Data collected in this study describe novel metabolic events for multiple important drugs of abuse, culminating in detection methods and mechanistic descriptors useful to both medical and forensic investigators when examining the toxicology associated with cocaine, methamphetamine, and morphine.