Duke Forum for Law & Social Change Symposium: Keynote Address

In this report a model was constructed in order to determine how a number of covariates influence the gross domestic product, GDP. The covariates were chosen depending on their expected influence on GDP, for example education and life expectancy. The data used in this report are collected from the World Bank. The model to describe GDP has been calculated using multiple line arregression. In order to reach a reliable final model the number of covariates has been gradually decreased to eliminate insignificant covariates. In order to minimize the error term and find a reliable model the Baysian Information Criterion has been used together with hypothesis testing. At a 95% confidence interval the final model could predict 111 of 139 countries GDP. The influences of the covariates in the final model is well in line with the expectations. For instance a positive relationship between GDP and education is observed.I denna rapport har en modell tagits fram som beskriver hur bruttonationalprodukten, BNP, påverkas av ett antal kovariater, t.ex. befolkningens utbildning och livslängd. Data för BNP samt för samtliga kovariater har inhämtats från Världsbanken. Modellen för att beskriva BNP har tagits frammed hjälp av multipel linjär regression. För att nå en slutgiltig modell med god tillförlitlighet har antalet kovariater successivt minskats för att utesluta insignifikanta kovariater. För att minimera feltermen och hitta en tillförlitlig modell har Baysian Information Criterion använts i kombination med hypotestest. Den slutgiltiga modellenkunde med ett konfidensintervall på 95% prediktera 111 av 139 länders BNP. Den slutgiltiga modellen stämmer väl med den förväntade bilden av kovariaternas inverkan på BNP. Exempelvis syns en positiv relation mellan utbildning och ett lands BNP

In-plate toxicometabolomics of single zebrafish embryos

Toxicometabolomic studies involving zebrafish embryos have become increasingly popular for linking apical endpoints to biochemical perturbations as part of adverse outcome pathway determination. These experiments involve pooling embryos to generate sufficient biomass for metabolomic measurement, which adds both time and cost. To address this limitation, we developed a high-throughput toxicometabolomic assay involving single zebrafish embryos. Incubation, microscopy, embryo extraction, and instrumental metabolomic analysis were all performed in the same 96-well plate, following acquisition of conventional toxicological endpoints. The total time for the assay (including testing of 6 doses/n= 12 embryos per dose plus positive and negative controls, assessing conventional endpoints, instrumental analysis, data processing and multivariate statistics) is <14 days. Metabolomic perturbations at low dose were linked statistically to those observed at high dose and in the presence of an adverse effect, thereby contextualizing omic data amongst apical endpoints. Overall, this assay enables collection of high resolution metabolomic data in a high throughput manner, suitable for mode of action hypothesis generation in the context of pharmaceutical or toxicological screening

Amitriptyline at an environmentally relevant concentration alters the profile of metabolites beyond monoamines in gilt-head bream

The antidepressant amitriptyline is a widely used selective serotonin reuptake inhibitor that is found in the aquatic environment. The present work investigates alterations in the brain and liver metabolome of gilt-head bream (Sparus aurata) following exposure at an environmentally relevant concentration (0.2 µg/L) of amitriptyline for 7 days. Analysis of variance-simultaneous component analysis (ASCA) was used to identify metabolites that distinguished exposed from control animals. Overall, alterations in lipid metabolism suggest the occurrence of oxidative stress in both brain and liver, a common adverse effect of xenobiotics. However, alterations in the amino acid arginine were also observed, likely related to the nitric oxide system, which is known to be associated with the mechanism of action of antidepressants. Additionally, changes on asparagine and methionine levels in brain and pantothenate, uric acid, formylisoglutamine/N-formimino-L-glutamate levels in liver could indicate alteration of amino acid metabolism in both tissues, and the perturbation of glutamate in liver suggests that the energy metabolism was also affected. These results revealed that environmentally relevant concentrations of amitriptyline perturbed a fraction of the metabolome which is not typically associated with antidepressant exposure in fish.Peer ReviewedPostprint (author's final draft

LongITools:Dynamic longitudinal exposome trajectories in cardiovascular and metabolic noncommunicable diseases

The current epidemics of cardiovascular and metabolic noncommunicable diseases have emerged alongside dramatic modifications in lifestyle and living environments. These correspond to changes in our "modern" postwar societies globally characterized by rural-to-urban migration, modernization of agricultural practices, and transportation, climate change, and aging. Evidence suggests that these changes are related to each other, although the social and biological mechanisms as well as their interactions have yet to be uncovered. LongITools, as one of the 9 projects included in the European Human Exposome Network, will tackle this environmental health equation linking multidimensional environmental exposures to the occurrence of cardiovascular and metabolic noncommunicable diseases

LongITools: Dynamic longitudinal exposome trajectories in cardiovascular and metabolic noncommunicable diseases

The current epidemics of cardiovascular and metabolic noncommunicable diseases have emerged alongside dramatic modifications in lifestyle and living environments. These correspond to changes in our “modern” postwar societies globally characterized by rural-to-urban migration, modernization of agricultural practices, and transportation, climate change, and aging. Evidence suggests that these changes are related to each other, although the social and biological mechanisms as well as their interactions have yet to be uncovered. LongITools, as one of the 9 projects included in the European Human Exposome Network, will tackle this environmental health equation linking multidimensional environmental exposures to the occurrence of cardiovascular and metabolic noncommunicable diseases

LongITools: Dynamic longitudinal exposome trajectories in cardiovascular and metabolic noncommunicable diseases

The current epidemics of cardiovascular and metabolic noncommunicable diseases have emerged alongside dramatic modifications in lifestyle and living environments. These correspond to changes in our “modern” postwar societies globally characterized by rural-to-urban migration, modernization of agricultural practices, and transportation, climate change, and aging. Evidence suggests that these changes are related to each other, although the social and biological mechanisms as well as their interactions have yet to be uncovered. LongITools, as one of the 9 projects included in the European Human Exposome Network, will tackle this environmental health equation linking multidimensional environmental exposures to the occurrence of cardiovascular and metabolic noncommunicable diseases.</p

Toxicometabolomics and biotransformation product screening in single zebrafish embryos

Over the last decade environmental agencies worldwide have escalated their work to phase out animal testing for the purposes of chemical regulation. Meanwhile the number of commercially available chemicals and the requirements for hazard assessments have both increased, creating a large need for substitution of traditional in vivo assays with in vitro tests. One example of this is the replacement of the OECD acute toxicity test of adult fish (test guideline [TG] 203) with zebrafish embryos (TG 236). With new insights into the toxicological properties of chemicals, the demand on these replacement tests is also changing character with a shifted focus towards mechanistic understanding of toxicity. The omics sciences encompass a group of analytical methods which have proven to be very powerful for unveiling of mechanistic information of biochemical processes. Metabolomics is one of the younger members of this family and entails the large-scale analysis of endogenous metabolites and their perturbation in living organisms. The overall objective of this thesis was to develop modifications to the TG236 OECD assay to obtain omic data suitable for use in chemical hazard assessment. To achieve this goal, we started by developing a targeted and non-targeted metabolomics workflow and evaluated the performance of the two types of analysis (Paper I). We also evaluated the efficiency of three signal drift correction approaches, which is an important step in data quality improvement for non-targeted analysis, and reported previously unlisted biochemicals present in NIST reference material. In Paper II we applied the workflow in Paper I to a newly developed, in-plate extraction method for single zebrafish embryos which were exposed to the pharmaceutical and environmental pollutant propranolol. Data processing workflows were developed to overcome challenges arising from the occurrence of the exposure compound and its biotransformation products (or in-source fragments of these) in the final multivariate statistical models, obscuring their outputs and prediction capabilities. Once developed, the workflow allowed us to detect several probable modes-of-action of propranolol in zebrafish, and link them to apical endpoints in the embryos, which were then confirmed through thorough literature searches. The final output from the models was ultimately used to determine a benchmarking dose based on metabolomics endpoints for the first time. In Paper III, the data processing workflow from Paper II was modified to capture propranolol biotransformation products. A total of 7 structures were identified, of which 4 were confirmed with authentic standards, all from the datasets generated in Paper II. In Paper IV we combined the workflows from Papers I, II and III and applied them to the pharmaceutical carbamazepine, which occurs at high concentrations in wastewater treatment plant effluents. Through this approach we determined several modes-of-action for carbamazepine in zebrafish embryos and measured biotransformation products in both embryos and exposure water. Overall, this thesis demonstrated the possibilities of high-throughput chemical mode-of-action determination in single zebrafish embryos using targeted and non-targeted liquid chromatography mass spectrometry, data filtering scripts and multivariate statistics while simultaneously screening for biotransformation products

Simulation driven design of timber bolster in fibre composite

The primary objective of this thesis is to investigate a simulation and optimisation based methodology using fibre composite materials to lower the weight of timber bolsters. The timber bolsters secure the timber from falling off the truck during loading and transport. A lighter forestry truck is beneficial for several reasons such as increased payload and fuel efficiency and a decreased environmental impact. This thesis includes a concept study for a bolster made of fibre composites. Carbon and glass fibres together with polyurethane were chosen as material system and the recommended manufacturing methods were pultrusion and resin transfer moulding. A study of the economy related to the timber transport was conducted during the concept phase to investigate the potential business case. The thesis also includes an optimisation of the generated concept. The optimisation focused on geometry and fibre layup. By the use of optimisation the weight was reduced from the initial 136 kg of aluminium to 87 kg of glass and carbon fibre. The optimised design was compared with today’s aluminium bolsters and indicated that the composite bolster is realistic from an economic perspective. A methodology for analysing bolted joints in fibre composites was developed. The analysis was made using the finite element method and resulted in a comparison between different failure criteria. Based on the results it can be concluded that the prediction of failure differs significantly depending on used failure criterion and tests are needed for verification. Finally a simulation was made to verify the structures response to an impact. The simulation was compared with calculations using energy equations showing a fairly good agreement.Det huvudsakliga syftet med detta examensarbete var att använda metodik baserad på simulering och optimering samt fiberkompositmaterial för att minska vikten på timmerbankar. Timmerbankar används för att lastsäkra timmer på lastbilar under lastning och transport. En lättare lastbil är fördelaktig av flera anledningar som t.ex. ökad kapacitet för nyttolast och bränsleeffektivitet samt en minskad miljöpåverkan. Examensarbetet inkluderar en konceptstudie för en timmerbanke i fiberkomposit. Kolfiber och glasfiber tillsammans med polyuretan valdes som material. Pultrusion och resin transfer moulding rekommenderades som tillverkningsmetoder. En studie av ekonomin relaterad till timmertransport genomfördes under konceptstudien för att undersöka om konceptet har potential att vara ekonomiskt gångbart. Examensarbetet innehåller även en optimering av det genererade konceptet. Optimeringen fokuserade på geometri samt kompositlaminatets fiberriktningar och stackningsordning. Genom användning av optimering minskades vikten på banken från dagens 136 kg i aluminium till 87 kg med glas och kolfiber. Den optimerade banken jämfördes med en existerande aluminiumbanke ur ett ekonomiskt perspektiv och slutsatsen är att med de givna antagandena har den optimerade konstruktionen större ekonomisk potential. En metod för att analysera skruvförband i komposit utvecklades och olika brottkriterier har undersökts. Analysen genomfördes med finita elementmetoden och resulterade i en jämförelse mellan olika brottkriterier. Baserat på resultaten kan det konstateras att prediktering av brott påverkas avsevärt av använt brottkriterium och att verifierande provning behövs. Slutligen genomfördes en simulering för att verifiera strukturens respons vid en slag last. Simuleringen jämfördes med beräkningar baserade på energiekvationer och på påvisade skaplig överenstämmelse