Computational analysis of the genetic and environmental contributions to disease-related human phenotypes: From predicting adverse lipid response of HIV patients receiving antiretroviral therapy to genome-wide association studies of cardiovascular and lipid related disorders

Genetic variants influence the risk to develop certain diseases or give rise to differences in drug response. Recent progresses in cost-effective, high-throughput genome-wide techniques, such as microarrays measuring Single Nucleotide Polymorphisms (SNPs), have facilitated genotyping of large clinical and population cohorts. Combining the massive genotypic data with measurements of phenotypic traits allows for the determination of genetic differences that explain, at least in part, the phenotypic variations within a population. So far, models combining the most significant variants can only explain a small fraction of the variance, indicating the limitations of current models. In particular, researchers have only begun to address the possibility of interactions between genotypes and the environment. Elucidating the contributions of such interactions is a difficult task because of the large number of genetic as well as possible environmental factors.In this thesis, I worked on several projects within this context. My first and main project was the identification of possible SNP-environment interactions, where the phenotypes were serum lipid levels of patients from the Swiss HIV Cohort Study (SHCS) treated with antiretroviral therapy. Here the genotypes consisted of a limited set of SNPs in candidate genes relevant for lipid transport and metabolism. The environmental variables were the specific combinations of drugs given to each patient over the treatment period. My work explored bioinformatic and statistical approaches to relate patients' lipid responses to these SNPs, drugs and, importantly, their interactions. The goal of this project was to improve our understanding and to explore the possibility of predicting dyslipidemia, a well-known adverse drug reaction of antiretroviral therapy. Specifically, I quantified how much of the variance in lipid profiles could be explained by the host genetic variants, the administered drugs and SNP-drug interactions and assessed the predictive power of these features on lipid responses. Using cross-validation stratified by patients, we could not validate our hypothesis that models that select a subset of SNP-drug interactions in a principled way have better predictive power than the control models using "random" subsets. Nevertheless, all models tested containing SNP and/or drug terms, exhibited significant predictive power (as compared to a random predictor) and explained a sizable proportion of variance, in the patient stratified cross-validation context. Importantly, the model containing stepwise selected SNP terms showed higher capacity to predict triglyceride levels than a model containing randomly selected SNPs. Dyslipidemia is a complex trait for which many factors remain to be discovered, thus missing from the data, and possibly explaining the limitations of our analysis. In particular, the interactions of drugs with SNPs selected from the set of candidate genes likely have small effect sizes which we were unable to detect in a sample of the present size (<800 patients).In the second part of my thesis, I performed genome-wide association studies within the Cohorte Lausannoise (CoLaus). I have been involved in several international projects to identify SNPs that are associated with various traits, such as serum calcium, body mass index, two-hour glucose levels, as well as metabolic syndrome and its components. These phenotypes are all related to major human health issues, such as cardiovascular disease. I applied statistical methods to detect new variants associated with these phenotypes, contributing to the identification of new genetic loci that may lead to new insights into the genetic basis of these traits. This kind of research will lead to a better understanding of the mechanisms underlying these pathologies, a better evaluation of disease risk, the identification of new therapeutic leads and may ultimately lead to the realization of "personalized" medicine.

Body image perception and weight-related behaviour among adolescents of the Seychelles

Background: We examined one's own body image perception and its association with reported weight-related behavior among adolescents of a rapidly developing country in the African region. Methods: We conducted a school-based survey of 1432 students aged 11-17 years in the Seychelles. Weight and height were measured, and thinness, normal weight and overweight were assessed along standard criteria. A self-administered and anonymous questionnaire was administered. Perception of body image was assessed using both a closed-ended question (CEQ) and the Stunkard's pictorial silhouettes (SPS). Finally, a question assessed voluntary attempts to change weight. Results: Overall, 14.1% of the students were thin, 63.9% were normal-weight, and 22.0% were overweight or obese. There was fair agreement between actual weight status and self-perceived body image based on either CEQ or SPS. However, a substantial proportion of the overweight students did not consider themselves as overweight (SPS: 24%, CEQ: 34%) and, inversely, a substantial proportion of the normal-weight students considered themselves as too thin (SPS: 29%, CEQ: 15%). Among the overweight students, an adequate attempt to lose weight was reported more often by boys and girls who perceived themselves as overweight vs. not overweight (72-88% vs. 40-71%, p <0.05 for most comparisons). Among the normal-weight students, an inadequate attempt to gain weight was reported more often by boys and girls who perceived themselves as thin vs. not thin (27-68% vs. 11-19%, p <0.05). Girls had leaner own body ideals than boys. Conclusions: We found that substantial proportions of overweight students did not perceive themselves as overweight and/or did not want to lose weight and, inversely, that many normalweight students perceived themselves as too thin and/or wanted to gain weight: this points to forces that can drive the upwards overweight trends. Appropriate perception of one's weight was associated with adequate weight-control behavior, although not strongly, emphasizing that appropriate weight perception is only one of several factors driving adequate weight-related behavior. These findings emphasize the need to address appropriate perception of one's own weight and adequate weight-related behavior in adolescents for both individual and community weight-related interventions.

Impact of quality and environmental investment on business competitiveness and profitability: The case of travel agencies

Few studies have examined the combined effect of implementing quality and environmental management within the service sector. This void is more evident if we focus on segments in which small businesses predominate and even more so if we look for highly competitive sectors that are very variable and that have high business mortality. After analysing 198 surveys of Spanish travel agency managers using structural equations, it can be concluded that practices of quality management have a significant direct impact on business competitiveness but not on this business's financial results, at least directly. However, there is a significant relationship between environmental management practices and economic benefits. This article suggests that commitment to quality and the environment can allow small businesses in the service sector to have a competitive advantage that will separate surviving and ceased operations, particularly in sectors that are rapidly evolving and highly competitive.

pH Sensitive surfactants from lysine: assessment of their cytotoxicity and environmental behavior

The toxicity and environmental behavior of new pH-sensitive surfactants from lysine are presented. Three different chemical structures are studied: surfactants with one amino acid and one alkyl chain, surfactants with two amino acids on the polar head and one alkyl chain, and gemini surfactants. The pH sensitivity of these compounds can be tuned by modifying their chemical structures. Cytotoxicity has been evaluated using erythrocytes and fibroblast cells. The toxic effects against these cells depend on the hydrophobicity of the molecules as well as their cationic charge density. The effect of hydrophobicity and cationic charge density on toxicity is different for each type of cells. For erythrocytes, the toxicity increases as hydrophobicity and charge density increases. Nevertheless, for fibroblasts cationic charge density affects cytotoxicity in the opposite way: the higher charge density, the lower the toxicity. The effect of the pH on hemolysis has been evaluated in detail. The aquatic toxicity was established using Daphnia magna. All surfactants yielded EC50 values considerably higher than that reported for cationic surfactants based on quaternary ammonium groups. Finally, their biodegradability was evaluated using the CO2 headspace test (ISO 14593). These lysine derivatives showed high levels of biodegradation under aerobic conditions and can be classified as"readily biodegradable compounds".

Molecular method for the characterization of Coxiella burnetii from clinical and environmental samples: variability of genotypes in Spain

Background: Coxiella burnetii is a highly clonal microorganism which is difficult to culture, requiring BSL3 conditions for its propagation. This leads to a scarce availability of isolates worldwide. On the other hand, published methods of characterization have delineated up to 8 different genomic groups and 36 genotypes. However, all these methodologies, with the exception of one that exhibited limited discriminatory power (3 genotypes), rely on performing between 10 and 20 PCR amplifications or sequencing long fragments of DNA, which make their direct application to clinical samples impracticable and leads to a scarce accessibility of data on the circulation of C. burnetii genotypes. Results: To assess the variability of this organism in Spain, we have developed a novel method that consists of a multiplex (8 targets) PCR and hybridization with specific probes that reproduce the previous classification of this organism into 8 genomic groups, and up to 16 genotypes. It allows for a direct haracterization from clinical and environmental samples in a single run, which will help in the study of the different genotypes circulating in wild and domestic cycles as well as from sporadic human cases and outbreaks. The method has been validated with reference isolates. A high variability of C. burnetii has been found in Spain among 90 samples tested, detecting 10 different genotypes, being those adaA negative associated with acute Q fever cases presenting as fever of intermediate duration with liver involvement and with chronic cases. Genotypes infecting humans are also found in sheep, goats, rats, wild boar and ticks, and the only genotype found in cattle has never been found among our clinical samples. Conclusions: This newly developed methodology has permitted to demonstrate that C. burnetii is highly variable in Spain. With the data presented here, cattle seem not to participate in the transmission of C. burnetii to humans in the samples studied, while sheep, goats, wild boar, rats and ticks share genotypes with the human population.

Environmental requirements and environmental management system of boiler plant supplier

Työn tärkeimpänä tavoitteena oli edistää ympäristöjärjestelmän laatimista Kvaerner Pulping, Power divisioonan Kattilat-liiketoimintayksikölle. Lisäksi tavoitteena oli tarkastella yritykseen kohdistuvia ympäristövaatimuksia ja niiden vaikutusta yrityksen toimintaan. Aluksi työssä tarkasteltiin ympäristöjärjestelmästandardien sisältöjä ja niiden eroja. Työssä käsiteltiin myös erilaisia elinkaarijohtamisen malleja, joita voidaan hyödyntää yrityksen kokonaisvaltaisessa ympäristöjärjestelmässä. Työssä tarkasteltiin myös sidosryhmien vaikutusta yrityksen ympäristötoimintaan. Kattilalaitostoimittajan tärkeimpiä asiakkaita ovat sellu- ja paperiteollisuus. Näihin yrityksiin on kohdistunut runsaan kymmenen vuoden aikana paineita ympäristötoiminnan tehostamiseksi. Tämän kehityksen seurauksena vastaavat tehostamispaineet ovat siirtymässä myös alihankkijoille, kuten kattilaitostoimittajille. Tehokkaan ympäristöjohtamisen takaamiseksi työssä määriteltiin ympäristövastuut ja –valtuudet sekä ympäristöpäämäärät ja –tavoitteet. Lisäksi tunnistettiin yrityksen toimintaan liittyvät ympäristönäkökohdat ja –riskit. Työn yhteydessä laadittiin ympäristöjärjestelmän luonnos, ja se sisältää jatkuvan parantamisen periaatteen. Työn yhteydessä laadittiin lisäksi Kvaerner Pulping Oy:n koelaitokselle ympäristölupahakemus. Työssä on kuvattu koelaitosta ja sen ympäristölupahakemukseen liittyviä asioita esimerkkinä parantuneesta ympäristöasioiden hoidosta.

Morph-specific genetic and environmental variation in innate and acquired immune response in a color polymorphic raptor.

Genetic color polymorphism is widespread in nature. There is an increasing interest in understanding the adaptive value of heritable color variation and trade-off resolution by differently colored individuals. Melanin-based pigmentation is often associated with variation in many different life history traits. These associations have recently been suggested to be the outcome of pleiotropic effects of the melanocortin system. Although pharmacological research supports that MC1R, a gene with a major role in vertebrate pigmentation, has important immunomodulatory effects, evidence regarding pleiotropy at MC1R in natural populations is still under debate. We experimentally assessed whether MC1R-based pigmentation covaries with both inflammatory and humoral immune responses in the color polymorphic Eleonora's falcon. By means of a cross-fostering experiment, we disentangled potential genetic effects from environmental effects on the covariation between coloration and immunity. Variation in both immune responses was primarily due to genetic factors via the nestlings' MC1R-related color genotype/phenotype, although environmental effects via the color morph of the foster father also had an influence. Overall, dark nestlings had lower immune responses than pale ones. The effect of the color morph of the foster father was also high, but in the opposite direction, and nestlings raised by dark eumelanic foster fathers had higher immune responses than those raised by pale foster fathers. Although we cannot completely discard alternative explanations, our results suggest that MC1R might influence immunity in this species. Morph-specific variation in immunity as well as pathogen pressure may therefore contribute to the long-term maintenance of genetic color polymorphism in natural populations.

Local perception and use of the multifunctionality of water tanks in two villages of Tamil Nadu, South India

Using data from free listings and a survey in two villages of Tamil Nadu, India, we discuss local perceptions and uses of water tanks, a traditional irrigation infrastructure. We hypothesize that both farmers and nonfarmers perceive and use water tanks for purposes other than irrigation. We found that informants recognized the importance of water tanks for irrigation, but also acknowledged other socioeconomic uses and ecological functions. Marginal sectors (i.e., Scheduled Castes) use tank resources in more diverse ways than other sectors of the population. Findings are relevant for development. International organizations working on the revival of water tanks aim to transfer water management to farmers for the purpose of irrigation. By recognizing that tanks benefit people other than farmers and in ways other than providing irrigation water, organizations working on tank rejuvenation could achieve a more equitable management of tank resources.

The influence of genetic and environmental factors among MDMA users in cognitive performance

This study is aimed to clarify the association between MDMA cumulative use and cognitive dysfunction, and the potential role of candidate genetic polymorphisms in explaining individual differences in the cognitive effects of MDMA. Gene polymorphisms related to reduced serotonin function, poor competency of executive control and memory consolidation systems, and high enzymatic activity linked to bioactivation of MDMA to neurotoxic metabolites may contribute to explain variations in the cognitive impact of MDMA across regular users of this drug. Sixty ecstasy polydrug users, 110 cannabis users and 93 non-drug users were assessed using cognitive measures of Verbal Memory (California Verbal Learning Test, CVLT), Visual Memory (Rey-Osterrieth Complex Figure Test, ROCFT), Semantic Fluency, and Perceptual Attention (Symbol Digit Modalities Test, SDMT). Participants were also genotyped for polymorphisms within the 5HTT, 5HTR2A, COMT, CYP2D6, BDNF, and GRIN2B genes using polymerase chain reaction and TaqMan polymerase assays. Lifetime cumulative MDMA use was significantly associated with poorer performance on visuospatial memory and perceptual attention. Heavy MDMA users (>100 tablets lifetime use) interacted with candidate gene polymorphisms in explaining individual differences in cognitive performance between MDMA users and controls. MDMA users carrying COMT val/val and SERT s/s had poorer performance than paired controls on visuospatial attention and memory, and MDMA users with CYP2D6 ultra-rapid metabolizers performed worse than controls on semantic fluency. Both MDMA lifetime use and gene-related individual differences influence cognitive dysfunction in ecstasy users.

Risk perception and stages of smoking acquisition = Percepción de riesgo y etapas de iniciación en el consumo de tabaco

The purpose of this descriptive survey was to investigate the risk perceptions of smoking in a sample of 1,510 Spanish adolescents(49.1% males; mean age = 14.03; SD = 1.28). In addition, the present research categorised adolescents into one of the fourstages of smoking acquisition, as described by the Transtheoretical Model of Change (TMC): Precontemplation (notthinking about trying smoking in the next 6 months), Contemplation (thinking about trying smoking in the next 6 months), Preparation (thinking about starting smoking in the next 30 days) and Action (smokers), by gender and age. The results showed that age and risk perceptions are important variables in the progression through the stages of change towards regular tobacco consumption (Action stage). These results clearly demonstrate the importance of starting antismoking campaigns at an early age to prevent smoking acquisition or the thought of starting in the near future. These findings also highlight the need to continuously remind adolescents about the negative consequences of smoking

Salir de la escuela: entre la tradición y la educación ambiental para la sostenibilidad = Excursions from school: between tradition and environmental education for sustainability

Las actividades escolares fuera del centro constituyen una marca de calidad del pasado y del presente educativo, y tienen que seguir siéndolo en el futuro. A partir de una investigación cualitativa se identifican las razones aducidas por enseñantes para salir del aula y, con ejemplos concretos, quedan plasmados algunos de los objetivos perseguidos, así como otros que se añaden a la propia actividad. Se identifican salidas vivenciales y otras más experimentales, se reconocen valores positivos, pero también se echa en falta un trabajo más coherente con los principios actuales de la educación ambiental. Precisamente esta educación es la propuesta como el camino a seguir para renovar objetivos, técnicas y procedimientos para salir del aula

Financial and Environmental Impacts of a Dry Port to Facilitate Competitiveness of Two Major Transit Seaports of Finland

Environmental problems and issues have received more and more attention during the last decades. Reasons for this are different increased external costs such as congestion, CO2 emission, noise and accident costs. Transportation sector is the only sector with increasing external costs. The EU will increase its attention in decreasing the external costs of transport. Aim of this research was to find out if a dry port solution could decrease costs of transport, especially external costs. Dry port concept is an intermodal transport system, where inland transport between port and dry port is performed by rail transport instead of traditional road transport. In addition, dry ports offer similar services as ports. Research is conducted by performing a literature review about dry port concept and costs of transport, especially external costs of transport. Financial and environmental impacts of the dry port concept are studied by comparing costs of road and rail transport by cost accounting and with a simulation model. Location of dry port is researched with gravitational models. Results of the literature review are that rail transport is environmentally friendlier mode of transport than road transport. Cost model and simulation model show that if only costs of freight movement are considered, rail transport is more inexpensive transport mode than road transport in terms of internal and external costs. Because of that dry port concept could decrease costs of transport, especially external costs. Results of gravitational models are that city of Kouvola is in a good position to be a dry port. Russian transit traffic through Finland improves location of Kouvola to be a dry port.

Sensitive spectrophotometric assessment of carbofuran using dapsone as a new chromogenic reagent in formulations and environmental samples

A simple, sensitive and selective spectrophotometric method for the assessment of carbofuran in various formulations and in environmental water samples is described. The method is based on the coupling of hydrolyzed carbofuran with diazotized dapsone in alkaline medium at 0 ­ 4° C which gives orange red colored product having the absorption maximum at 480 nm. The product is stable for 48 h. Beer's law is obeyed in the concentration range of 0.1 ­ 4.0 µg ml-1. The molar absorptivity and Sandell's Sensitivity are 5.0 x 10(4) L mol-1 cm-1 and 4.4 ng cm-2 respectively. The method is highly reproducible and is confirmed by RSD values (1.144 %). From the recovery studies it is found that this method is accurate and it can be successfully employed for the determination of carbofuran.