Since the mid-1990s, formal verification has become increasingly important because it can provide guarantees that a software system is free of bugs and working correctly based on a provided model. Verification of biological and medical systems is a promising application of formal verification. Human neural networks have recently been emulated and studied as a biological system. Some recent research has been done on modelling some crucial neuronal circuits and using model checking techniques to verify their temporal properties. In large case studies, model checkers often cannot prove the given property at the desired level of generality. In this thesis, we provide a model using the Coq proof assistant and prove some properties concerning the dynamic behavior of some basic neuronal structures. Understanding the behavior of these modules is crucial because they constitute the elementary building blocks of bigger neuronal circuits. By using a proof assistant, we guarantee that the properties are true in the general case, that is, true for any input values, any length of input, and any amount of time. In this thesis, we define a model of human neural networks. We verify some properties of this model starting with properties of neurons. Neurons are the smallest unit in a human neuronal network. In the next step, we prove properties about functional structures of human neural networks which are called archetypes. Archetypes consist of two or more neurons connected in a suitable way. They are known for displaying some particular classes of behaviours, and their compositions govern several important functions such as walking, breathing, etc. The next step is verifying properties about structures that couple different archetypes to perform more complicated actions. We prove a property about one of these kinds of compositions. With such a model, there is the potential to detect inactive regions of the human brain and to treat mental disorders. Furthermore, our approach can be generalized to the verification of other kinds of networks, such as regulatory, metabolic, or environmental networks.

The research presented in this dissertation focuses on improvements made to lithium niobate leaky-mode modulators for both holographic video and optogenetic applications. The specific improvements found herein are: (1) characterization of leaky-mode modulators to decrease driver bandwidth to match that of commodity graphics processing units, (2) the implementation of surface relief gratings as input couplers to replace rutile prism coupling, (3) the addition of backside surface relief gratings to create an orthogonal output face for the leaky-mode modulator, and (4) the creation of superimposed surface relief gratings in lithium niobate to enable multiple wavelength coupling at a single input angle. These advancements for leaky-mode modulators open avenues in display technologies and optogenetics. As a display technology, the leaky-mode modulator can not only be used more effectively in holographic monitors, but can stand alone as a transparent near-eye display. In regards to optogenetics, these technologies allow for the creation of a highly advanced light delivery method, with multiple illumination angles through non-mechanical steering, a large output area to probe size ratio, and support for simultaneous multiple wavelength output in both common and disparate locations.

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Alterations in composition and function of human gut microbiota can affect physiological processes and are known to be associated with many diseases including inflammatory bowel disease, hypertension, asthma and colon cancer. Complex interactions between gut microbiota, environmental toxins, nutrients and host genetics may result in an increased permeability of the gut, which is closely linked to the presence of adverse metabolic conditions. As a consequence, translocation of bacterial DNA into the blood circulation increases in patients with obesity. Obesity is a growing health problem worldwide and often paired with severe secondary complications, such as type 2 diabetes or cardiovascular problems. A main feature of disease progression is a chronic low-grade inflammation of adipose tissue which contributes to the development and aggravation of insulin resistance and many of the underlying mechanisms are still unknown. Although data from mice studies suggest that the presence of bacterial components in adipose tissue can support these processes, human studies on this subject are lacking. In my thesis entitled ``Bacterial translocation to adipose tissue in metabolic diseas'' I provide evidence supporting the initial hypothesis, namely that bacterial DNA is present in adipose tissue, even after stringent controlling for contaminants. To this end, I established a wet lab routine protocol to eliminate contamination as well as a bioinformatics pipeline accounting for contamination by subtracting negative controls. Briefly, this included the use of lab ware and reagents UV-treated for at least 90 minutes, the use of breath protection, extra-long gloves and single-use lab coats as well as working under a sterile laminar flood hood in a clean lab free of any PCR products. The bioinformatics pipeline employed commonly used 16S rRNA gene analysis tools including qiime2, phyloseq and DESeq2 as well as decontam, a novel tool to extract negative controls. Observed quantity of bacterial DNA was in the range of 1 to 10 pg/µg total isolated genomic DNA, which is equivalent to about 0.01 to 0.7% of bacterial cells per human cell. The highest quantity was present in subcutaneous adipose tissue, followed by mesenteric adipose tissue. Bacterial amount correlated with adipose tissue macrophages and PPARG expression in omental and with IL1B and TNF expression in subcutaneous adipose tissue. Mesenteric adipose tissue showed the highest diversity of the observed genera. The most commonly observed phyla in all tissues were Proteobacteria and Firmicutes, which is in line with previously published data on blood bacterial DNA. Still, many genera were predominantly found in specific tissues, e.g. Enterobacter in subcutaneous and Acinetobacter in omental adipose tissue. I further showed that the distribution of observed features could partially be explained by markers of insulin resistance (HOMA-IR, HbA1c) and inflammation (IL-6, TNFa, macrophages) and that certain genera, such as Rhodoferax or Lactobacillus are associated with type 2 diabetes status. In first functional approaches I demonstrated that concentrations of bacterial DNA in the observed range are sufficient to stimulate an inflammatory response in immortalized subcutaneous adipocytes derived from a healthy donor. The effect was most prominent after four hours of treatment and increased in a dose-dependent matter. One of the aims in the present study was to determine levels of gut leakage by measuring zonulin, the most commonly used biomarker for intestinal permeability in humans, and analyze possible associations with adipose tissue bacterial signature. As there are few well-conducted studies on circulating zonulin levels in patients with metabolic diseases, I first performed a correlation study in the available and metabolically well-characterized Sorbs cohort. Circulating zonulin correlated significantly positive with BMI, fasting glucose, triglycerides and cholesterol and negatively with HOMA-IS, high density lipoprotein and circulating adiponectin levels. Albeit these strong correlations with markers of glucose and lipid metabolism supported previously reported findings, the results pointed to some inconsistencies. As zonulin is reported to be pre-haptoglobin 2 (preHP2), and about 15% percent of a typical western European population are homozygous for haptoglobin 1, they should not express zonulin at all. I confirmed in the Sorbs cohort previously reported distributions of haptoglobin genotypes and showed that the target of the only commercially available zonulin ELISA kit was not related to haptoglobin genotype, therefore presumably not measuring zonulin/ preHP2. Subsequently, I identified properdin as a possible target by employing mass spectrometry approaches. Properdin is structurally related to haptoglobin, as both proteins belong to the mannose-associated serine protease family, however further experiments are needed to validate a possible functional resemblance. In regard to bacterial translocation two adipose tissue depots were of notable interest due to their close proximity to the gastrointestinal tract. Mesenteric adipose tissue is located around the small intestine and the adipose tissue of the appendices epiploicae, small chunks of fat also called epiploic adipose tissue, are directly attached to the colon. After a thorough literature research I could also assert that both adipose tissues were rarely analyzed in the context of obesity. Therefore they were extensively investigated by measuring gene expression of adipo(cyto)kines, circulating inflammatory markers and analyzing adipocyte size and adipose tissue macrophages. Furthermore, a ``multiomics'' characterization was conducted and by analyzing transcriptome and methylome data I could identify epiploic adipose tissue as a tissue of interest in regard to type 2 diabetes and insulin resistance, which was further confirmed by untargeted proteomics data. Contrary to initial assumptions, I observed only a slight increase in translocation of bacterial DNA and no increased inflammation, as measured by tissue specific TNF and IL6 expression as well as adipose tissue macrophage infiltration. However, both transcriptome and proteome profiles allowed a clear discrimination of patients with and without insulin resistance which was most distinct in epiploic adipose tissue. Compared to other fat depots, epiploic adipose tissue exhibited a discriminable metabolic profile whereas mesenteric adipose tissue was more similar to omental-visceral adipose tissue. Most strikingly, epiploic adipose tissue showed a strong increase in leptin expression and, in general, the upregulation of various metabolic pathways involved in sugar, amino acid or sphingolipid metabolism. In accord with the leaky gut hypothesis high expression of lipopolysaccharide binding protein and various pathways involved in chemokine signaling were observed. In summary, I did not observe an increase in bacterial DNA or adipose tissue macrophages, but demonstrated elevated inflammatory signals such as increased chemokine or IL-8 signaling which are linked with an overall increase of metabolic processes and an increased expression of various adipokines. Epiploic adipose tissue might have a watch dog function by being the first adipose tissue sensing and forwarding certain (microbial) stimuli from the large intestine to the host. In the last part of my thesis I addressed a possible role of the HLA genomic region on the development of type 2 diabetes. The influence of HLA genetics on type 2 diabetes has been under debate for several decades, since HLA was recognized to largely contribute to type 1 diabetes heritability. However, studies remained inconclusive due to lacking cohorts with sample sizes providing sufficient statistical power for association analyses. More recently, animal studies suggested MHC class II proteins as crucial factors mediating adipose tissue inflammation and insulin resistance. The sample size of the leaky gut cohort was insufficient to determine any correlation between HLA class II genotypes and the presence or type of bacteria in adipose tissue due to the high variability in the observed genomic region. Yet, I had access to three large population-based cohorts which allowed me to analyze associations between HLA class II alleles and type 2 diabetes. Therefore HLA genotypes of the LIFE-Adult (N=4649), LIFE-Heart (N=4815) and Sorbs (N=949) cohort were imputed from SNP genotyping data and analyzed for association with type 2 diabetes. In a meta-analysis including all three cohorts, I identified a protective effect for the well-established type 1 diabetes protective haplotype DRB1*15:01~DQA1*01:02~DQB1*06:02 and confirmed DRB1*07:01~DQA1*02:01~DQB1*03:03 as a risk haplotype in non-insulin treated diabetes. These results suggest that the genetic foundation of both type 1 and 2 diabetes shares common elements involving the HLA class II locus. In conclusion, to the best of my knowledge, I provide in my work the first contaminant-aware identification of bacterial DNA in human adipose tissue and highlight the importance of analyzing novel adipose tissue depots by showing that fat of the appendices epiploicae, previously only considered to have a cushioning function, is metabolically active and possibly involved in the development of insulin resistance.

Background: Today, women and men do not share leadership positions equally within the organizational context. In turn, leadership, particularly transformational leadership, which is mainly used by female leaders, is essential for organizations. Within the organization, the leaky pipeline is a reason why female leaders face gender-specific challenges in their roles as leaders. Further, some aspects provide support for women in the organizational context. However, there is a gap in the literature regarding how these female leaders can overcome these gender-specific challenges.   Purpose: This thesis aims to investigate how Swedish female middle managers can navigate the hinders and helpers they experience within the organizational context.    Method: The thesis was conducted in a qualitative approach with an interpretivist paradigm. The findings were collected through semi-structured interviews with a sample of Swedish female middle managers in the context of private companies and the municipal sector. The empirical findings were analyzed and coded systematically using Gioia’s et al. (2013) method. As a result, a framework emerged based on the existing literature in line with an inductive approach.    Conclusion: This study proposes the Female Leaders Navigation Framework as a help for the female leaders to navigate in the organizational context. Four navigations: 1) Mindset, 2) Awareness, 3) Preparation, and 4) Communication can be implemented by the female leader to navigate the perceived hinders and helpers in the organizational context.

Enligt "Leaky gut”-hypotesen är ökad translokation av gramnegativa bakterier genom tarmslemhinnan förknippad med neuroimmuna störningar. Denna ökning av permeabiliteten i tarmslemhinnan kan orsakas av störning i tarmfloran efter antibiotikabruk eller sjukdom, vilket kan leda till inflammatoriska processer. Inflammation har sedan tidigare blivit förknippad med allvarlig depressiv störning och självmordsbeteende. Studiens syfte var att utveckla och validera en qPCR-baserad metod för att kunna detektera DNA från tarmbakterier i blod/plasma, som ett tecken på translokering av bakterier. Två primerpar för amplifiering av 16S rDNA utreddes genom observation av PCR-reaktioner med humant och bakteriellt DNA. Det mest optimala primerparets PCR effektiviteten och linjäriteten testades. Metodens funktion kontrollerades sedan med helblod och plasma med tillsats av exogent DNA från E.coli. Den utvecklade qPCR metoden detekterar bakterie DNA i prov med 10 kopior/µl, vilket gör den tillräckligt känslig för detektion av tarmbakterier i blod. / According to the "Leaky gut" hypothesis, increased translocation of gram-negative bacteria through the intestinal mucosa is associated with neuroimmune disorders. The increase of permeability of the intestinal mucosa may be caused by disturbance of the intestinal flora after antibiotic use or disease, which can lead to inflammatory processes. Inflammation has previously been associated with major depressive disorder and suicidal behavior. The purpose of the study was to develop and validate a qPCR-based method for detecting DNA from intestinal bacteria in blod/plasma, as a sign of decreased mucosal integrity. Two different primer pairs, targeting 16S rDNA, were investigated by observing their PCR reactivity with human and bacterial DNA. PCR efficiency and linearity were tested on the most optimal primer pair. The function of the method was then verified with whole blood and plasma with the addition of exogenous DNA from E.coli. The developed qPCR method detects bacterial DNA in samples at 10 copies/µl, making it sufficiently sensitive for detection of intestinal bacterial DNA in blood.

Virtual reality (VR) head-mounted displays provide a high definition, immersive experi-ence to the viewer. However, most existing technologies have flaws like bulky design and vergence-accommodation conflict that may cause stress in the neck muscles, posture issues, nausea, motion sickness and dizziness. Similarly, augmented reality (AR) displays, which use transparent light modulators, exist, but they possess low field of view and a limited number of discrete depth planes when wide field of view and continuous depth would be ideal. The ultimate goal of my research is use leaky mode waveguide devices to create wide-view angle, transparent near eye holographic displays for AR with strong continuous depth accommo-dation and no vergence-accommodation conflict. The leaky mode platform has the advantages of low fabrication complexity and monolithic design. Unfortunately, bottom-exit leaky mode devices to date have had produced relatively small view angles. The specific objective of this thesis is to explore the use of static structures in leaky mode waveguide devices to increase field of view. In this work I will show that it is theoretically possible to achieve increased field of view with increased resolution and no overlap among view zones. My specific contributions to this research include: i) modeling of integrated Lithium Nio-bate device and testrig that contains quartz substrates on MATLAB, ii) construction of a simulator of the integrated device which involved fabrication of a prototype test rig for intermediate laser induced structures, iii) fabrication of intermediate diffractive structures by photolithography and by femto-second laser ablation which involved - 100 sample test, dose test and creation of sample femtograting on Lithium Niobate substrate. Results which are obtained from the modelling of inte-grated device and the prototype simulator are analysed. This analysis is provided in my manuscript to show how precise is the prototype simulator when compared with integrated device. The ob-tained result of the integrated device is 52.4541° where as it is 69.113° for prototype simulator. This effort was reported in a publication and presentation at Brigham Young University, Provo, Utah.

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