Synopsis My research work is focused on: (i) development of novel Fast NMR methods in solution state and their application to metabolomics and small molecules. (ii) NMR based metabolic study of human IVF to assess embryo viability for implantation. The major components of the embryo growth media were identified for evaluating the embryo quality. Described below are the projects carried out towards the dissertation of my PhD. Chapter 1 describes NMR methods which are the foundation stones for new Fast NMR methods developed. Typical 1D and 2D NMR experiments used in metabolomics and statistical methods for analysis are described. A few applications of metabolomics are also covered in the chapter. Chapter 2 describes a new Fast NMR method based on polarization sharing and parallel acquisition using the dual receiver system. The method developed helps in acquiring simultaneously three 2D NMR spectra: 2D [13C-1H] HETCOR, 2D [1H-1H] TOCSY and 2D [13C-1H] HSQC-TOCSY in a single data set. This method achieves a time saving of about two fold. All the experiments are acquired on molecules with natural abundance of 13C. The method was used to assign the side chain atoms (1H and 13C) of two important peptides. i) 12 amino acid residue peptide, which is a part of central linker domain of Human Insulin like Growth Factor Binding Protein-2 known to play a vital role in the IGF system and ii) a 18 amino acid residue peptide which acts as an antimicrobial agent. Chapter 3 describes extension of the Fast NMR method described in chapter 2. The method is combined with G-matrix Fourier Transform NMR spectroscopy. In this method we have acquire simultaneously two 2D NMR experiments and one reduced dimensional 3D experiment. The three experiments are 2D [13C-1H] HETCOR, 2D [1H-1H] TOCSY and GFT (3,2)D [13C-1H] HSQC-TOCSY, which provide complementary information for rapid assignments. GFT (3,2)D [13C-1H] HSQC-TOCSY gives 3D correlations in a 2D manner facilitating high resolution and unambiguous assignments. The experiments were applied for complete assignment of 21 unlabeled metabolite mixtures corresponding to the Innovative Sequential medium (ISM1) used for culturing human embryos for IVF. Further, a 13C multiplicity edition block is added to the method to simplify the resonances assignment in GFT (3,2)D [13C-1H] HSQC-TOCSY. Taken together, experiments provide time gain of order of magnitudes compared to conventional data acquisition. Chapter 4 of the thesis describes a metabolomics study of Human in-vitro fertilization to assess viable embryos of implantation potential using NMR as non-invasive tool. NMR study included the analysis of 127 embryo culture media (Innovative Sequential Media-1) and 29 controls (culture media without embryo) of both day-2 and day-3 transferred. The embryos were divided into 3 categories 1) implanted (successful) 2) transferred not-implanted (unsuccessful) 3) not transferred based on morphological studies. All NMR experiments were acquired with CPMG (T2 filter) incorporated in 1D 1H presaturation pulse scheme. The study was based on estimation of lactate, pyruvate and alanine levels in the embryo culture media (ISM1). The study reveals higher uptake of pyruvate and high pyruvate/alanine ratios in case of implanted embryos compared to one which failed to implant. Present study provides pyruvate/alanine ratio as a biomarker to select the embryos with high implantation potential. The method combined with morphology based assessment or with other biomarkers can be serve as a powerful tool to assess the embryo quality. Chapter 5 describes a novel NMR method for rapid characterization of translation diffusion of molecules in solution either in mixture or pure form. Unlike acquisition of several 2D [13C-1H] HSQC experiments with varying gradients to get diffusion measurement, a single 2D [13C-1H] HSQC is sufficient to measure the diffusion coefficients which is in the linewidths of peaks. The method uses the idea of accordion NMR spectroscopy, wherein gradients are linearly co-incremented with 13C chemical shift evolution period during t1. The methodology speeds up the acquisition by replacing series of 2D [13C-1H] HSQC with single 2D constant time [13C-1H] HSQC. The method was used to monitor the diffusion of metabolites in a time-resolved manner during polymerization of SDS-PAGE gel. Using this method, it was possible to detect the presence of oligomers of diphenylalanine (FF) during its self assembly to form nanotubular structures.

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This paper investigates the potential of augmented reality (AR) as a navigational aid for individuals with Alzheimer’s disease (AD), offering innovative solutions to the evolving challenges of AD care. As the disease progresses, patients often require more assistance and may transition to care centers, resulting in reduced independence. Prior to this, home-based care aims to stimulate cognitive functions and preserve autonomy. To enhance their freedom and mobility, it is proposed to leverage AR technology to create a first-person navigational aid addressing the unique needs of AD patients. The research confronts two primary challenges: firstly, exploring the design of AR navigational aids customized for individuals with Alzheimer’s disease adapted to outdoor use. Then, it aims to develop an outdoor localization system for the HoloLens 2 and evaluate its performance. Despite limitations induced by the approximate positioning, various types of aids compatible with the technical constraints faced have been envisioned. A set of features was implemented using the optical see-through AR headset HoloLens 2. These features included two distinct types of holograms (Arrow and Wind) and the ability to catch user attention prior to turns, allowing us to explore the effectiveness of these design choices. They were evaluated through a user study involving 15 healthy participants. Usability and task load were measured with Nasa-TLX and SUS questionnaires. An approximate positioning for outdoor use of the HoloLens 2 was elaborated using a smartphone as a GPS receiver, and a Kalman filter for filtering and fusion with IMU data. This enables to reach positioning accuracy at the meter level. This research demonstrates the promising utility of AR in assisting navigation in outdoor environments. Despite few significant results, the Arrow hologram appears to be a better fit for usability and users’ personal preferences. Further research is needed to get significant results on the impact of adaptive aids. The outdoor use of AR navigational aids is still limited by the poor visibility of holograms outdoors and low positioning accuracy. / Denna artikel utforskar potentialen hos förstärkt verklighet (AR) som navigationshjälpmedel för personer med Alzheimers sjukdom (AD) och erbjuder innovativa lösningar inom AD-vård. När sjukdomen fortskrider behöver patienterna mer hjälp och kan övergå till vårdcentraler, vilket minskar deras självständighet. Hemvård strävar efter att stimulera kognitiva funktioner och bevara autonomi. Vi föreslår utnyttja AR-teknologi för en skräddarsydd navigeringshjälp i första person för AD-patienters behov. Forskningen möter två utmaningar: att utforska AR-navigeringshjälpmedel för personer med Alzheimers sjukdom och anpassade för utomhusanvändning. Vi strävar efter att utveckla utomhuslokaliseringssystem för HoloLens 2 och utvärdera prestanda. Trots begränsningar på grund av ungefärlig positionering kan vi föreställa oss hjälpmedel som är kompatibla med tekniska begränsningar. Vi använde HoloLens 2 med funktioner som två hologramtyper och användaruppmärksamhetsfångst före svängar, utvärderat med 15 deltagare. Vi skapade ungefärlig positionering för HoloLens 2 utomhus med en smartphone som GPS-mottagare, med Kalman-filtrering och IMU-fusion för meter-noggrannhet. Forskningen visar AR:s lovande nytta i utomhusnavigering. Trots få signifikanta resultat verkar pilhologrammet passa användbarhet och preferenser bättre. Mer forskning behövs för att bedöma adaptiva hjälpmedels effekter. Användningen av AR-navigeringshjälpmedel utomhus begränsas av dålig synlighet och låg positionsnoggrannhet. / Cet article explore le potentiel de la réalité augmentée (RA) comme aide à la navigation pour les personnes atteintes de la maladie d’Alzheimer (MA), offrant une solution novatrice aux défis en constante évolution des soins liés à la MA. À mesure que la maladie progresse, les patients ont souvent besoin d’une assistance accrue et sont transférés dans des centres de soins, ce qui diminue leur indépendance. Avant cela, les soins à domicile visent à stimuler leurs fonctions cognitives et à préserver leur autonomie. Dans cette optique, nous proposons d’utiliser la RA pour créer une aide à la navigation à la première personne adaptée aux besoins spécifiques des patients atteints de la MA. La recherche aborde deux défis principaux : la conception d’aides à la navigation en RA pour les personnes atteintes de la MA, adaptées à une utilisation en extérieur, et le développement d’un système de localisation en extérieur pour HoloLens 2, suivi de son évaluation. Malgré les limitations liées au positionnement approximatif, nous avons envisagé différents types d’aides compatibles avec ces contraintes techniques. Nous avons mis en place un ensemble de fonctionnalités en utilisant le casque de RA HoloLens 2. Ces fonctionnalités incluent deux types d’hologrammes (Flèche et Vent) et la capacité à attirer l’attention de l’utilisateur avant les virages, nous permettant d’explorer l’efficacité de ces choix de conception. Ils ont été évalués lors d’une étude avec 15 participants en bonne santé. Nous avons élaboré une méthode de positionnement approximatif pour une utilisation en extérieur de l’HoloLens 2 en utilisant un smartphone comme récepteur GPS, avec un filtre de Kalman pour le filtrage et la fusion avec des données inertielles, permettant d’atteindre une précision de positionnement au mètre. Cette recherche démontre l’utilité prometteuse de la RA dans l’assistance à la navigation en extérieur, bien que des recherches supplémentaires soient nécessaires pour obtenir des résultats significatifs sur l’impact des aides adaptatives. L’utilisation des aides à la navigation en RA en extérieur est encore limitée par la visibilité réduite des hologrammes en extérieur et la faible précision du positionnement.

Biologisk ålder (BA) har nyligen fått ökad uppmärksamhet att fördjupa förståelsen kring åldersrelaterade sjukdomar och dess behandlingar, eftersom åldersrelaterade förändringar utgör en grundläggande gemensam nämnare för dessa tillstånd. Medan kronologisk ålder (CA) mäts i år, kan biologisk ålder (BA) mätas på många olika sätt. I det här mastersarbetet användes blodbaserade biomarkörer som korrelerar med CA för att skapa uppskattningar av BA, med algoritmerna ‘PhenoAge’, ‘Klemera-Doubal metoden’ och ‘Homeostatic Dysregulation’. Biomarkörerna valdes ut genom Pearson och Spearmankorrelation med CA separat för varje kön. Dessutom validerades biomarkörerna mot mortalitet. Kohorten AMORIS (Apolipoprotein-relaterad dödlighetsrisk) användes för att beräkna tre olika biologiska åldersmått med hjälp av BioAge-paketet. För att undvika kollinearitet användes residualerna från dessa biologiska åldersmått, som representerar avvikelsen av BA från CA. PhenoAge-residualerna valdes för vidare undersökning på grund av deras robusthet. Sambandet mellan BA-residualer, särskilt PhenoAge-residualer, och Alzheimers sjukdom och relaterade demenssjukdomar (ADRD) utvärderades med Cox proportionella hazardmodeller. Justeringar gjordes för kön, utbildningsnivå och socioekonomisk status. Stratifiering för två åldersgrupper, över 65 och under 65, samt kön utfördes för två olika modeller. Modellens överensstämmelse varierade, över lag var den bättre för vaskulär demens och sämre för Alzheimers sjukdom. En ökad riskkvot hittades särskilt för vaskulär demens (PhenoAge HR=1.086, 95% CI=1.074 to 1.099), och till viss grad även för andra demenstyper men inte för Alzheimers sjukdom. Stratifiering efter ålder och kön visade varierande hazardkvoter, vilket tyder på olika riskprofiler bland olika demografiska grupper. En ökad risk för vaskulär demens noterades särskilt i åldersgruppen under 65 och bland män. Dessa differentierade risker belyser vikten av BA-markörer för att identifiera ökad risk för demensundergrupper och bekräftar värdet av att inkludera BA i bedömningen av ADRD för användning inom precisionsmedicin. / Biological age (BA) has recently gained increased attention as a means of deepening the understanding of the development of treatments for age-related diseases, as age-related changes serve as the fundamental commonality among these conditions. While chronological age (CA) is measured in years, BA can be measured in a wide variety of ways. In this thesis blood biomarkers correlated with CA were used as input to create BA estimates, with the algorithms PhenoAge, Klemera-Doubal method and Homeostatic Dysregulation. The serum biomarkers were selected by Pearson and Spearman correlation with CA separately per sex. The cohort AMORIS (Apolipoprotein-related MOrtality RISk) was used to calculate three different BA scores with the help of the BioAge package. To avoid collinearity, the residuals from these BA scores, which represent the deviation of BA from CA, were employed. The PhenoAge residuals were selected for further investigation due to their robustness. Association between BA residuals, particularly PhenoAge residuals, and Alzheimer’s disease and related dementias (ADRD) was assessed using Cox proportional hazard models. Adjustment was done for sex, education level and socioeconomic status. Stratification for two age groups, over 65 and under 65, as well as sex was done for two different models. The model concordance varied, overall, it was better for vascular dementia and worst for Alzheimer's disease. An increased hazard ratio was found especially for vascular dementia (PhenoAge HR=1.086, 95% CI=1.074 to 1.099), and to a lesser extent for other dementia types but not for Alzheimer's disease. Stratification by age and sex presented varied hazard ratios, suggesting different risk profiles among demographic groups. An increased risk for vascular dementia was especially noted in the age group under 65 and men. These differentiated risks, highlight the importance of BA markers in pinpointing elevated risks for dementia subtypes and affirm the value of incorporating BA into the assessment of ADRD for use in precision medicine.

This thesis is a contribution to feminist laboratory studies and a critical engagement with the natural sciences, or more precisely research on the biochemical workings and deadly relations of Alzheimer’s disease emanating from a year of field work in a Drosophila fly lab. The natural sciences have been a point of fascination within the field of gender studies for decades. Such sciences produce knowledge on what gets to count as nature and natural, healthy or sick, normal or not, and they have done it with great societal authority and impact throughout European modernity. However, feminist technoscience scholars argue that science and knowledge is socially produced, and political too. Concepts such as nature, animal, human, body, sex, and life itself are not simply given natural realities but phenomena processed through the naturecultures of the laboratory. Situated within such theoretical and methodological approaches, this thesis wonders how scientific facts about Alzheimer’s disease are made in the lab today. What kinds of realities, bodies and ethico-political concerns are enacted? Who gets to live and who gets to die in everyday laboratory practices? Theoretically, the thesis is grounded, particularly, within Karen Barad’s agential realism and posthumanist performativity, and as such it accounts for human and nonhuman entanglements through which AD is performed in the lab in relational ways. In other words, the thesis explores how AD is enacted in the bodies of transgenic fruit flies (Drosophila melanogaster), as these flies embody the disease, live and die with it. Last but not least, the thesis explores the materialities of death, dying, embodiment and biological waste in a biochemistry lab as constitutive parts of the produced knowledge about AD. / Denna avhandling utgör ett bidrag till feministiska laboratoriestudier och är en kritisk analys av naturvetenskaperna. Närmare bestämt är det en feministisk studie av forskning om Alzheimers sjukdom, dess biokemiska verkningar och dödliga relationer utifrån ett års fältarbete som labbtekniker i ett fluglabb. Naturvetenskaperna har under decennier fascinerat genusforskare. Dessa discipliner formar kunskapen om vad som räknas som natur och naturligt, hälsa och sjukdom, normalt eller inte, och de har gjort så med stor samhällelig auktoritet genom Europeisk modernitet. Forskare inom feministiska teknovetenskapliga studier har länge hävdat att vetenskap också är social praktik med politiska implikationer. Begrepp som natur, djur, mänskligt eller kropp, kön och livet självt kan inte tas för givna utan formas också i laboratoriets naturkultur. Med utgångspunkt i sådana feministiska teknovetenskaplig teoribildningar och metodologiska utgångspunkter bearbetar denna avhandling frågor om hur vetenskapliga fakta om Alzheimers sjukdom skapas i laboratoriet idag. Vilka kroppar, verkligheter och etisk-politiska förhållningssätt aktualiseras? Vem får leva och vem får dö i vardagliga laboratoriepraktiker? Teoretiskt bygger avhandlingen framför allt på Karen Barads agentiella realism när den diskuterar sammanvävningen mellan mänskligt och icke-mänskligt, samt det som kallas posthumanistisk performativitet, i relation till Alzheimers sjukdom som den förkroppsligas i transgena fruktflugor (Drosophila melanogaster) i laboratoriet. I särskilt fokus står relationerna som skapas inom den biokemiska forskningen kring död, biologiskt avfall och kroppslighet.

Alzheimer's disease (AD) was first described more than 100 years ago and is today the most common cause of dementia. It is one of the progressive neurodegenerative diseases that affect 47 million people around the world between the ages of 60 and 90. One of the contributing factors to AD is extracellular amyloid – β (Aβ) plaques that form as a result of protein aggregation. These Aβ proteins are neurotoxic, leading to degeneration of brain neurons and loss of cognitive abilities. Because AD largely affects society, researchers are constantly working to find a cure, which currently does not exist. The purpose of this study was to use Drosophila melanogaster as a living organism model for the expression of two types of Aβ proteins related to AD, Arctic (Glu22Gly) and TandemAβ, and to study the survival of these AD flies when Bovine serum albumin (BSA) was added to the fly food. The hypothesis was that BSA would be effective in slowing down and/or preventing formation of toxic Aβ-aggregates. The focus was therefore to investigate whether the AD flies would live longer if they were allowed to eat Bovine serum albumin and whether the soluble/insoluble Aβ levels in these flies would decrease in comparison to the control AD flies that were not allowed to eat BSA. The effect of BSA on toxicity was evaluated using survival assay on male flies and the levels of soluble/insoluble Aβ were evaluated using Meso Scale Discovery (MSD) on female flies. In both experiments, the following six groups of flies were examined: myow1118 ± BSA; myoArctic ± BSA; myoTandemAβ ± BSA. Conclusions from the studies are that the survival of AD flies could not be extended by adding 0.61 mM BSA to the food, rather the data showed a weak but significant toxic effect in the presence of BSA in the AD flies. However, MSD data showed a reduction of insoluble Aβ aggregates and an equilibrium shift from insoluble Aβ aggregates to soluble Aβ aggregates in the presence of BSA in the AD flies. Equilibrium shifts were particularly detectable in Myo-TandemAβ flies fed with BSA. In Myo-Arctic flies fed with BSA only reduction of insoluble Aβ could be detected. This shows that it is not the amount of Aβ aggregates that is decisive for toxicity, but rather the presence of specific aggregates that have toxic properties. If BSA shows good results in further studies, it could be used in the future to improve AD symptoms in patients.