Regulering av gener involvert i lipidmetabolisme i ulike vev og livsstadier i laks

Atlantic salmon is an important source of essential omega-3 fatty acids in human diets; however, omega-3 content in farmed salmon has been decreasing over the past decade due to the replacement of fish oil in aquafeeds with more sustainable and less expensive plant oil. To alleviate this, knowledge based breeding and feeding strategies need to be employed to produce nutritious salmon high in omega-3 in a sustainable and commercially viable way. These strategies require a genome wide understanding of lipid metabolism regulation. The work presented here brings us one-step closer to this goal through the development of an advanced cell culture systems (paper I), functional annotation of lipid metabolism genes (paper II), and interrogation of lipid metabolism regulation across life stages and tissues using transcriptomics in combination with two salmon trials (papers II and III). In paper I, we aim to establish precision cut liver slice culture (PCLS) as a platform for studying lipid metabolism in Atlantic salmon. To accomplish this, we carried out three main experiments: (i) a time course to identify culturing associated effects, (ii) a fatty acid and insulin supplementation experiment to test the liver slice response, and (iii) a primary cell culture experiment to benchmark PCLS culture against traditional cell culture and whole liver. Overall, liver slices acclimatize to the cell culture environment after three days, they actively respond to insulin and fatty acids in the media in a liver-like way, and liver slices are closer to liver in vivo than primary cell culture in terms of expression of lipid metabolic pathway genes and liver marker genes. In papers II and III, we aim to characterize changes in lipid metabolism-related gene expression across tissues and life stages in Atlantic salmon. Paper II involves the functional annotation of lipid metabolism genes and identification of genome wide trends in lipid metabolism regulation in liver and gut across diets and life stages. Metabolic plasticity in liver decreases after transition to seawater and lipid metabolism-related gene expression shifts from ‘liver centric’ biosynthesis in freshwater to ‘gut centric’ digestion and absorption in seawater. Paper III focuses more on how lipid metabolism changes during smoltification and subsequent seawater transfer. Lipid metabolism related gene expression generally decreases in smolts before transition to seawater. Additionally, shortened photoperiod likely does not influence smoltification-associated changes in lipid metabolism gene expression.Atlantisk laks er en viktig kilde til essensielle omega-3-fettsyrer for mennesker, men omega-3-innholdet i oppdrettslaks har gradvis sunket de siste 10 årene. Denne nedgangen i sunne omega-3-fettsyrer skyldes at fiskeolje i fôret har blitt erstattet med mer bærekraftige planteoljer. To mulige mottiltak er å avle frem laks som er bedre til å lagre eller lage omega-3 fettsyrer, eller finne nye fôrsammensetninger som sikrer høyt innhold av omega-3. Dette krever dybdeforståelse av hvordan laksen regulerer lipidmetabolismen, som er temaet for dette doktorgradsarbeidet. Avhandlingen beskriver et nyskapende system for dyrking av tynne skiver av vev (artikkel I), funksjonell annotering av gener involvert i lipidmetabolismen (artikkel II), og et dypdykk i genregulering av lipidmetabolismegener på tvers av livsstadier og vev (artikkel II og III). Artikkel I etablerer leversnittkultur som laboratoriemetode for å interaktivt studere lipidmetabolisme i laks. Arbidet inkluderer (i) et molekylært tidsserie-studium av i hvilken grad leversnittet bevarer sin karakter over tid, (ii) in vitro tilførsel av fettsyrer og insulin for å gjenskape aspekter ved normal leverfunksjon, og (iii) sammenlignende analyse av leversnitt og primærcellekultur. Resultatene viser at leversnitt stabiliserte seg i in vitro-miljøet etter 3 dager, responderte realistisk på endringer i insulin og fettsyretilførsel, og oppfører seg mer likt intakt lever enn primærcellekultur gjør, betraktet gjennom genuttrykk i lipidmetabolske reaksjonsveier. Artikkel II og III karakteriserer endringer i genuttrykk for lipidmetabolisme over ulike livsstadier og vev i laks. Artikkel II annoterer funksjonen til lipidgener og beskriver genregulering i lever og tarm hos laks på plante- vs fiskeoljediett i ferskvann, under smoltifisering (den fysiologiske omstillingen til saltvann) og i sjø. Effekten av diettforskjeller på stoffskiftet i lever ble svakere etter overgang til sjøvann, mens transkripsjon av gener for lipidopptak i tarm øker i sjøvann relativt til ferskvann. Artikkel III fokuserer på hvordan lipidmetabolisme-genuttrykk endres gjennom smoltifiseringsprosessen. Her fant vi at det relative uttrykket til gener involvert i lipidmetabolisme gradvis synker i smolt før de overføres til sjøvann. Simulert årstidsvariasjon i daglengde påvirket ikke genuttrykket i lever

Navigating the string landscape with machine learning techniques

This thesis explores the possibility of using heuristic search algorithms from data science, namely genetic algorithms and reinforcement learning, to navigate the string landscape to uncover phenomenologically interesting constructions. Specifically, we apply these algorithms to construct holomorphic slope-stable vector bundles over Calabi-Yau three-folds. These vector bundles lead to the particle spectrum of the minimally supersymmetric standard model (plus uncharged moduli), via compactifications of the E8 × E8 heterotic string. We explore two types of vector bundles: sums of line bundles, which have been extensively explored in existing literature and thus serve as a benchmark for the effectiveness of the algorithms, and monad bundles, where only one quasi-realistic model was previously known. For both environments, these search algorithms were able to discover many models, while exploring as little as 10−19 of the total space. As an example of these methods in a simpler context, we also explored Froggatt-Nielsen models of quark masses

A Few Interventions and Offerings from Five Movement Lawyers to the Access to Justice Movement

We are five lawyers who occupy very different corners of justice work. We are civil rights, human rights, and criminal defense lawyers, and we have worked at and managed legal services programs. We have taught law at law schools and universities and have built our own organizations. We currently work in interdisciplinary spaces with community organizers, funders, and other stakeholders in the justice system. As diverse as our perspectives are, we share a common belief that any mobilization around access to justice fails if it does not center the vision and strategies of larger social justice movements. We share here our collective calls to action to the legal community—and the allies that support and resource legal services—to expand our mission beyond chasing a standard of fairness that is impossible to achieve as long as we have deeply embedded structural and systemic inequity. Instead, let us reimagine what our communities actually need to be safe, free, and to live in our fullest humanity. We believe the role of movement lawyers is to use the law as a tool of social change, at the direction of communities most impacted by injustice. When we focus our lawyering on listening to community organizers, clients, and activists with a broader vision for social change, we can become partners in transforming systems, rather than simply making them more hospitable

Observations on the action of Iodine

While I was resident physician in the wards of the Royal Infirmary, Edinburgh, Dr. Chalmers Watson suggested I should study the injection of iodine intravenously. I chose twelve cases at random, and the following is an account of the preparation used; the technique; and the results.The preparation used consisted of:- Iodine i drachm; Potassium Iodide 1 drachm; Distilled Water 5 ounces; Minims 20 of the above in 10 cc. Normal Saline was the quantity used for each injection, i.e. gr. 0.5 of Iodine.THE TECHNIQUE: The injection was given intravenously at 11 A.M. For some days prior to the injection all patients were placed on a uniform diet, etc. with a view to eliminating as far as possible any error arising from altered environment.Each experiment lasted three days.Observations were made on temperature, respiration rate, pulse rate, systolic and diastolic pressure; urine per hour (quantity, specific gravity, urea concentration, and abnormal constituents); influence on the leucocyte count; anti the Basal Metabolic Rate ( B.M.R.)Careful observations were taken at frequent intervals throughout each day, noting the patients general condition, size of thyroid, and any variations in the symptomatology, both subjective and objective.On the first day control observations were made. On the second day Iodine was administered intravenously at 11 A.M., and the results carefully studied; while on the third day observations were made on similar lines. For the following few days the patients" condition was carefully watched

Anomaly Detection in Time Series: Theoretical and Practical Improvements for Disease Outbreak Detection

The automatic collection and increasing availability of health data provides a new opportunity for techniques to monitor this information. By monitoring pre-diagnostic data sources, such as over-the-counter cough medicine sales or emergency room chief complaints of cough, there exists the potential to detect disease outbreaks earlier than traditional laboratory disease confirmation results. This research is particularly important for a modern, highly-connected society, where the onset of disease outbreak can be swift and deadly, whether caused by a naturally occurring global pandemic such as swine flu or a targeted act of bioterrorism. In this dissertation, we first describe the problem and current state of research in disease outbreak detection, then provide four main additions to the field. First, we formalize a framework for analyzing health series data and detecting anomalies: using forecasting methods to predict the next day's value, subtracting the forecast to create residuals, and finally using detection algorithms on the residuals. The formalized framework indicates the link between the forecast accuracy of the forecast method and the performance of the detector, and can be used to quantify and analyze the performance of a variety of heuristic methods. Second, we describe improvements for the forecasting of health data series. The application of weather as a predictor, cross-series covariates, and ensemble forecasting each provide improvements to forecasting health data. Third, we describe improvements for detection. This includes the use of multivariate statistics for anomaly detection and additional day-of-week preprocessing to aid detection. Most significantly, we also provide a new method, based on the CuScore, for optimizing detection when the impact of the disease outbreak is known. This method can provide an optimal detector for rapid detection, or for probability of detection within a certain timeframe. Finally, we describe a method for improved comparison of detection methods. We provide tools to evaluate how well a simulated data set captures the characteristics of the authentic series and time-lag heatmaps, a new way of visualizing daily detection rates or displaying the comparison between two methods in a more informative way