Indiana University-Purdue University Indianapolis (IUPUI) / Glutamate clearance by astrocytes is an essential part of physiological excitatory neurotransmission. Failure to adapt or maintain low levels of glutamate in the central nervous system is associated with multiple acute and chronic neurodegenerative diseases. The primary excitatory amino acid transporters (EAATs) in human astrocytes are EAAT1 and EAAT2 (GLAST and GLT-1 respectively in rodents). While the inhibition of a ubiquitously-expressed serine/threonine protein kinase, the calcium/calmodulindependent kinase (CaMKII) results in diminished glutamate uptake in cultured primary rodent astrocytes, the molecular mechanism underlying this regulation is unknown. In order to delineate this mechanism, we use a heterologous expression model to explore CaMKII regulation of EAAT1 and EAAT2. In transiently transfected HEK293T cells, pharmacological inhibition of CaMKII and overexpression of a dominant-negative version of CaMKII (Asp136Asn) reduces [3H]-glutamate uptake by EAAT1, without altering EAAT2 mediated glutamate uptake. Surprisingly, overexpression of a constitutively active autophosphorylation mutant (Thr287Asp) to increase autonomous CaMKII activity and a mutant incapable of autophosphorylation (Thr287Val) had no effect on either EAAT1 or EAAT2 mediated glutamate uptake. Pulldown of FLAGtagged glutamate transporters suggests CaMKII does not interact with EAAT1 or EAAT2. SPOTS peptide arrays and recombinant GST-fusion proteins of the intracellular N- and C-termini of EAAT1 identified two potential phosphorylation sites at residues Thr26 and Thr37 in the N-terminus. Introducing an Ala (a non-phospho mimetic) but not an Asp (phosphomimetic) at Thr37 diminished EAAT1-mediated glutamate uptake, suggesting that the phosphorylation state of this residue is important for constitutive EAAT1 function. In sum, this is the first report of a glutamate transporter being identified as a direct CaMKII substrate. These findings indicate that CaMKII signaling is a critical driver of homeostatic glutamate uptake by EAAT1. Aberrations in basal CaMKII activity disrupt glutamate uptake, which can perpetuate glutamate-mediated excitotoxicity and result in cellular death.

Predicting drug concentrations in the blood and at the site of action is the hottest topic in pharmacokinetics (PK). In vitro-in vivo extrapolation (IVIVE) and physiological based pharmacokinetics (PBPK) models are two major PK prediction strategies. However, both IVIVE and PBPK models are considered as immature methodologies due to their poor predictability. The goal of the research is to investigate the discrepancies within IVIVE and PBPK predictions according to first-principles: convection, diffusion, metabolism, and carrier-mediated transport. In Chapter 2, non-permeability limited hepatic elimination under perfusion steady state is examined. The well-stirred model is re-derived from the convection-dispersion-elimination equation when both dispersion and concentration gradient are ignored and re-named as the zero-gradient model. Pang and Rowland’s lidocaine data are re-analyzed. Their data analysis was based on an unfair comparison of the zero-gradient and parallel- tube models at two different efficiency number ranges. The interference of sensitivity greatly biased the comparison. I also show that both theoretical discussions and experimental results indicate that apparent intrinsic clearance and intrinsic clearance could be affected by blood flow and protein binding. In Chapter 3, I discuss permeability limited hepatic elimination under perfusion steady state. Permeability limited elimination is classified to diffusion dominated, carrier-mediated transport mediated, and mixed effects based on drug passage mechanisms. Each of these three drug passage classes is sub-divided to sink condition and finite volume condition based on the boundary conditions of drug passage. In Chapter 4, the discrepancies within IVIVE for both non-permeability limited and permeability limited drugs are explored. The deficiencies in assay design and data analysis of common in vitro metabolism assays are investigated. The scaling/converting equations for both non-permeability limited and permeability limited drugs are derived. In Chapter 5, I focus on transient PK models. Numerical analysis using finite difference and finite volume methods are introduced into the derivation and discussion of transient PBPK models. In addition, the use of partition coefficient in the non-eliminating tissue/organ models is discussed.

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Att Polismyndigheten har svårt att klara upp fall av dödligt våld i kriminella miljöer är ett problem som är vida känt i dagens Sverige. I kriminalstatistiken påvisas ett ökat skjutvapenvåld, och studier samt personliga utsagor vittnar om en utbredd tystnadskultur inom kriminella kretsar och utsatta områden. Denna studie uppmärksammar den problematik som finns kopplad till utredningar av dödligt våld i kriminella miljöer. Intervjuer har gjorts med fem utredare som är, eller nyligen har arbetat, med dessa ärenden inom Polismyndigheten. Materialet har analyserats med hjälp av en kvalitativ innehållsanalys, och resultatet har kopplats till teorierna rational choice, broken windows, samt organisatoriskt lärande. I resultatet har identifierats svårigheter kopplade den resursbrist som tydligt framkommit under studiens gång, där det efterfrågas ett större antal utredare samt bredare kompetens, kunskap och erfarenhet. Vidare har framkommit att det förekommer svårigheter i att få människor att vittna vid dessa typer av brott. Slutligen efterfrågas av intervjupersonerna större legala möjligheter i form av övervakning. / The purpose of this study was to examine what investigative difficulties are associated with investigations of lethal violence in criminal environments. We wanted to investigate which factors tend to complicate the work for Polismyndigheten. Furthermore, we discussed the consequences that the low rate of resolved cases has on society and how it's connected to crime prevention. The material was gathered from five semi-structured interviews and the result from these was analyzed with previous studies on the subject as well as rational choice theory, broken windows theory and organizational learning theory. The result showed that difficulties related to lack of resources was a clear theme in all the interviews. This is primarily connected to a need for more investigators in the relevant sections as well as a broader set of skills, knowledge and experience distributed over the entire workforce. Furthermore, the study showed that there is a problem regarding getting witnesses to give their statements to the police during investigations of lethal violence in criminal environments. Finally, greater legal possibilities regarding surveillance were identified as a part of the result.

Global renewable energy requirements rapidly increase with the transition to a fossil-free society. As a result, intermittent energy resources, such as wind- and solar power, have become increasingly popular. However, their energy production varies over time, both in the short- and long term. Hydropower plants are therefore utilized as a regulating resource more frequently to maintain a balance between production and consumption on the electrical grid. This means that they must be operated away from the design point, also known as the best-efficiency-point (BEP), and often are operated at part-load (PL) with a lower power output. Moreover, some plants are expected to provide a spinning reserve, also referred to as speed-no-load (SNL), to respond rapidly to power shortages. During this operating condition, the turbine rotates without producing any power. During the above mentioned off-design operating conditions, the flow rate is restricted by the closure of the guide vanes. This changes the absolute velocity of the flow and increases the swirl, which is unfavorable. The flow field can be described as chaotic, with separated regions and recirculating fluid. Shear layer formation between stagnant- and rotating flow regions can be an origin for rotating flow structures. Examples are the rotating-vortex-rope (RVR) found during PL operation and the vortical flow structures in the vaneless space during SNL operation, which can cause the flow between the runner blades to stall, also referred to as rotating stall. The flow structures are associated with pressure pulsations throughout the turbine, which puts high stress on the runner and other critical parts and shortens the turbine's lifetime. Numerical models of hydraulic turbines are highly coveted to investigate the detrimental flow inside the hydraulic turbines' different sections at off-design operating conditions. They enable the detailed study of the flow and the origin of the instabilities. This knowledge eases the design and assessment of mitigation techniques that expand the turbines' operating range, ultimately enabling a wider implementation of intermittent energy resources on the electrical grid and a smoother transition to a fossil-free society. This thesis presents the numerical study of the Porjus U9 model, a scaled-down version of the 10 MW prototype Kaplan turbine located along the Luleå river in northern Sweden. The distributor contains 20 guide vanes, 18 stay vanes and the runner is 6-bladed. The numerical model is a geometrical representation of the model turbine located at Vattenfall Research and Development in Älvkarleby, Sweden. The commercial software ANSYS CFX 2020 R2 is used to perform the numerical simulations. Firstly, the draft tube cone section of the U9 model is numerically studied to investigate the sensitivity of a swirling flow to the GEKO (generalized kω) turbulence model. The GEKO model aims to consolidate different eddy viscosity turbulence models. Six free coefficients are changeable to tune the model to flow conditions and obtain results closer to an experimental reference without affecting the calibration of the turbulence model to basic flow test cases. Especially, the coefficients affecting wall-bounded flows are of interest. This study aims to analyze if the GEKO model can be used to obtain results closer to experimental measurements and better predict the swirling flow at PL operation compared to other eddy viscosity turbulence models. Results show that the near-wall- and separation coefficients predict a higher swirl and give results closer to experimentally obtained ones. Secondly, a simplified version of the U9 model is investigated at BEP and PL operating conditions and includes one distributor passage with periodic boundary conditions, the runner and the draft tube. The flow is assumed axisymmetric upstream of the runner, hence the single distributor passage. Previous studies of hydraulic turbines operating at PL show difficulties predicting the flow's tangential velocity component as it is often under predicted. Therefore, a parametric analysis is performed to investigate which parameters affect the prediction of the tangential velocity in the runner domain. Results show that the model predicts the flow relatively well at BEP but has problems at PL; the axial velocity is overpredicted while the tangential is underpredicted. Moreover, the torque is overpredicted. The root cause for the deviation is an underestimation of the head losses. Another contributing reason is that the runner extracts too much swirl from the flow, hence the low tangential velocity and the high torque. Sensitive parameters are the blade clearance, blade angle and mass flow. Finally, the full version of the U9 model is analyzed at SNL operation, including the spiral casing, full distributor, runner and draft tube. During this operating condition, the flow is not axisymmetric; vortical flow structures extend from the vaneless space to the draft tube and the flow stalls between the runner blades. A mitigation technique with independent control of each guide vane is presented and implemented in the model. The idea is to open some of the guidevanes to BEP angle while keeping the remaining ones closed. The aim is to reduce the swirl and prevent the vortical flow structures from developing. Results show that the flow structures are broken down upstream the runner and the rotating stall between the runner blades is reduced, which decreases the pressure- and velocity fluctuations. The flow down stream the runner remains mainly unchanged.

Background: Higher protein diets, especially from animal sources, have seen a rise in popularity due to potential metabolic. This may have consequences for kidney function particularly in rising middle class populations who are allocating more income towards meat. The objective of this systematic review and meta-analysis was to evaluate the effects of higher versus lower protein intake on glomerular filtration rate (GFR) in adult populations without renal impairment. Methods: Search strategies were developed and electronic databases searched: MEDLINE and EMBASE. Data were extracted up until June 3, 2015. The main outcome measure was GFR and a random effect model (Cochrane’s Review Manager Version 5.3) was used to pool mean differences in GFR values. Results: Database searches yielded 25 trials from 1914 articles that were eligible for analysis based on inclusion/exclusion criteria. 12 studies were randomized controlled trials and 11 studies were crossover trials. As a result of data presented, 2 crossover studies were treated as 4 trials to result in 25 total trials. A total of 810 subjects from 25 trials were included in this systematic review and meta-analyses. The age of participants was 24-62 years and their BMI was 21-36 kg/m2. Higher protein compared to lower protein-containing diets were associated with increased GFR values [mean difference (MD): 8.33 ml/min (95% CI 4.87 to 11.79), P < 0.00001] but this was less pronounced when assessing change from baseline GFR values [MD: 4.71 ml/min (95% CI 0.06 to 9.36), P = 0.05]. Moreover, significant heterogeneity was present and funnel plot asymmetry indicated potential publication bias in both meta-analyses. Conclusion: Higher protein diets were associated with increased GFR, however, these results were inconclusive due to significant heterogeneity and overestimation by random effect analyses. There is still no clear evidence that high protein diets negatively impact renal function in healthy populations. / Thesis / Master of Science (MSc) / Globally, the leading causes of mortality in industrialized countries are cardiovascular disease (CVD), stroke, and type 2 diabetes (T2D). Deaths from these chronic diseases now outpace deaths due to malnutrition. Being overweight and obese increases the risk of both morbidity and mortality from CVD, stroke, and T2D. Global rates of overweight and obesity have now reached ‘epidemic’ proportions and the World Health Organization has stated that, “… [a] global epidemic of overweight and obesity – ‘globesity’ – is taking over many parts of the world. If immediate action is not taken, millions will suffer from an array of serious health disorders.” Over the past 20-30 years, the popularity of higher protein energy restricted diets have grown due to the potential benefits regarding weight loss, appetite regulation, and maintenance of lean (muscle) mass. Additionally, the expansion of the global ‘middle-class’ has resulted in families allocating more income towards meat products as a primary protein source in their diet. A health concern is that higher protein intake may have an adverse effect on kidney function. In individuals with chronic kidney disease, higher protein diets have been shown to result in further renal impairment. However, the effects of increased protein intake in healthy populations are unclear. The aim of this systematic review and meta-analysis was to compare higher versus lower protein diets on kidney function in healthy populations based on the literature to date. This was accomplished by looking at changes in glomerular filtration rate (the rate at which kidneys filter blood), which is the ‘gold standard’ marker of kidney function.

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The rights of tenants to the spaces that they are possessors of but do not hold titles to is contested in practice in large scale redevelopment projects. This thesis takes a look at two specific instances of urban district redevelopment and renewal in Malmö, Sweden: the slum clearance of Lugnet in the 1960s and the attempts to densify Holma in the present day. Using the concepts of the power of law, property and dispossession the thesis asks “how have the rights of tenants been taken into consideration?” This thesis finds that there is a great discrepancy between legal and philosophical constructs of property and ownership – that have been articulated in law well before the modern age – and the “dispossessory tendencies” prevalent in urban planning. It also finds that the codifying of tenant rights in the communicative model of planning has little relation to tenants rights as possessors – users – of their everyday spaces. These rights are challenged by ideas of the public good and the large scale of redevelopment projects. / Hyresgästers rättigheter till de platser som de besitter men inte innehar lagfarten till har i praktiken åsidosatts vid storskalig exploatering av bebyggda områden. Denna uppsats tittar närmare på två specifika fall av sådan exploatering, som berör hela stadsdelar i Malmö. Det första fallet är slumsaneringen av Lugnet i centrala Malmö på 1960-talet, och det andra är pågående försök att förtäta Holma i de södra delarna av Malmö. Utifrån begreppen makt, egendom och besittningsrätt ställs frågan “hur har hyresgästers rättigheter beaktats i dessa situationer?” Uppsatsen finner att det finns en stor diskrepans mellan de juridiska och filosofiska sätten att tänka kring egendom och ägandeskap – så som de har uttryckts i lag långt innan den moderna tidsåldern – och de bortträngande tendenserna som är inneboende i stadsplanering. I uppsatsen framkommer det också att fastställandet av hyresgästers rättigheter i planeringens kommunikativa process har liten koppling till hyresgästers rättigheter som besittare – dvs. brukare – av sina vardagsplatser. Dessa rättigheter utmanas av idéer om det allmännas bästa och storskaligheten på nybyggnationen.