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Idiopathic Pulmonary Fibrosis (IPF) is a debilitating respiratory disorder that is characterized by a progressive decline in lung function. Originating through unknown etiology, it is essentially an unchecked wound healing response that causes the build-up of excessive scar tissue in the lung interstitial tissue with a heavy toll on the patient’s respiratory capacity. Pro-fibrotic alternatively activated macrophages (M2) have been linked as an important contributor to the fibrotic remodeling of the lung. Previous Ask research indicates that targeting M2 macrophages is possible through the use of the Dectin-1 receptor, a transmembrane cell surface receptor found in high abundance on M2 macrophages. Activating the Dectin-1 receptor through the use of beta-glucan, a ligand the receptor has a high affinity for, initiates a pro-inflammatory response within the naturally immunosuppressive macrophage and can alter its activity to be less fibrogenic. Our data suggest that M2 polarization of naïve macrophages can be inhibited in vitro by beta-glucan microparticles. Additionally, we have found that polarized M2 macrophages adopt M1-like characteristics when treated with beta-glucan microparticles, in a process that is largely Dectin-1 dependent. M2 cell surface marker CD206, increased levels of which are associated with rapidly progressing IPF, shows significantly decreased frequency of expression in M2 macrophages treated with beta-glucan microparticles. Our assessment for cell-specific uptake of beta-glucan microparticles suggests an important role of the Dectin-1 receptor for significantly increased uptake in murine wild-type M2 macrophages relative to their Dectin-1 knockout counterpart. The use of beta-glucan microparticles as a potential anti-fibrotic therapeutic was assessed in the bleomycin model of fibrotic lung disease. Mice given bleomycin and treated with beta-glucan displayed decreased soluble collagen content and TGFB expression within lung homogenate relative to fibrotic bleomycin control mice. Overall, these results provide insight into the use of beta-glucan as a potential activity modulator of macrophage function in IPF and the possibility of its use as a therapeutic. / Thesis / Master of Science (MSc)

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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with worsening respiratory symptoms and physiological impairment. Pulmonary fibrosis is a chronic lung disease characterized by forming scar tissue (fibrosis) in the lungs. Alternatively activated macrophages (M2) known as pro-fibrotic are known to contribute to the fibrotic remodeling of the lung. In addition to the polarization of slices from naïve to pro-fibrotic, the addition of anti-fibrotic therapeutics reprogram slices back to a naïve condition. To polarize the slices, naïve slices are incubated with a previously investigated method in the lab known as the polarization cocktail. The polarization cocktail can be achieved by adding of IL-4, IL-6 and IL-13 to naïve(M0) slices in the Precision Cut lung slice (PCLS) model. For the therapeutic model, slices are incubated with the polarization cocktail and subsequently with the therapeutic. Our results have shown that the precision cut lung slice model can mimic previously investigated in-vivo experiments with the polarization cocktail. Secondly, the addition of therapeutics result in the slices exhibiting lower amounts of M2 markers and arginase activity concluding the model is suitable for the polarization and reprogramming of macrophages. / Thesis / Master of Science in Medical Sciences (MSMS)

Serotonin (5-hydroxytryptamine, 5-HT) as well as noradrenaline (NA) are key modulators of various fundamental brain functions including the control of appetite. While manipulations that alter brain serotoninergic signaling clearly affect body weight, studies implicating 5-HT transporters and NA transporters (5-HTT and NAT, respectively) as a main drug treatment target for human obesity have not been conclusive. The aim of this positron emission tomography (PET) study was to investigate how these central transporters are associated with changes of body weight after 6 months of dietary intervention or Roux-en-Y gastric bypass (RYGB) surgery in order to assess whether 5-HTT as well as NAT availability can predict weight loss and consequently treatment success. The study population consisted of two study cohorts using either the 5-HTT-selective radiotracer [11C]DASB to measure 5-HTT availability or the NAT-selective radiotracer [11C]MRB to assess NAT availability. Each group included non-obesity healthy participants, patients with severe obesity (body mass index, BMI, >35 kg/m2) following a conservative dietary program (diet) and patients undergoing RYGB surgery within a 6-month follow-up. Overall, changes in BMI were not associated with changes of both 5-HTT and NAT availability, while 5-HTT availability in the dorsal raphe nucleus (DRN) prior to intervention was associated with substantial BMI reduction after RYGB surgery and inversely related with modest BMI reduction after diet. Taken together, the data of our study indicate that 5-HTT and NAT are involved in the pathomechanism of obesity and have the potential to serve as predictors of treatment outcomes.

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POPULAR SCIENTIFIC SUMMARY Systemic lupus erythematosus (SLE) is not your average disorder. It behaves like a mischievous troublemaker, wreaking havoc throughout the body, causing inflammation that affects multiple organs. SLE presents a puzzle that keeps health care professionals worldwide intrigued, searching for answers amidst its complex of immunologic manifestations and clinical symptoms. While we’ve made progress in understanding SLE, its specific cause remains a mystery. What we do know is that SLE triggers a fascinating interplay between genetic, hormonal, and environmental factors in susceptible individuals. Macrophages, specialized white blood cells, can be likened to moody actors on a stage wearing different masks and wielding functional props. Among them are M1 macrophages, fiery troublemakers who provoke pro-inflammatory responses, and M2 macrophages, peacemakers striving for balance by generating anti-inflammatory responses. Then there is NRF2, the vigilante, normally held by its captor, KEAP1. However, when cells stress NRF2 manages to break free from KEAP1 and spring into action, embarking on a crucial journey into the cell nucleus where DNA is stored. Once inside, NRF2 binds specific regions of the DNA, promoting genes associated with protective activities, including antioxidative responses and detoxification processes, thereby shielding cells from further harm. Now, let us envision a therapeutic strategy that utilizes this; if we can deliberately unleashNRF2 on command, triggering a powerful cascade of antioxidative responses throughout the body,such a treatment would offer tremendous promise and serve as a paradigm for patients sufferingfrom chronic inflammation. But the question remains: Is it possible? In this study, we investigated the effects of certain chemicals on macrophages in a controlledlab environment. Our goal was to explore their potential for therapeutic purposes. Excitingly, wediscovered that these chemicals can indeed influence macrophages to produce a stronger antiinflammatory and antioxidant response. These findings could be promising for developing futuretreatments, especially in patients diagnosed with conditions such as SLE. / ABSTRACT Systemic lupus erythematosus (SLE) is a multifaceted, chronic autoimmune disorder that leads to inflammation and affects various organs. A wide range of immunologic manifestations and clinical symptoms characterizes SLE. While the specific cause remains unknown, it is thought to result from a combination of genetic susceptibility and the intricate interplay between environmental and hormonal factors. A significant subset of SLE patients also experience renal manifestation, lupus nephritis (LN), characterized by distinct inflammatory responses in which macrophages play a role. Macrophages exhibit different functional characteristics depending on their environment, and generally display two contrasting phenotypes; M1, which elicits proinflammatory responses, and M2, which generates anti-inflammatory responses Homeostasis is vital, yet environmental stress is inevitable. NRF2, a transcription factor known for its involvement in oxidative stress response, plays a pivotal role. Under basal conditions, NRF2 resides in the cytoplasm and is targeted for degradation by the protein KEAP1. However, during cellular stress, the NRF2-KEAP1 complex dissociates, allowing NRF2 to translocate into the nucleus where it binds specific regulatory regions of genes that promote cytoprotective activities. The NRF2 pathway has gained attention as a potential target for therapeutic strategies in inflammatory conditions, including SLE. This study aimed to assess the effects of certain chemical NRF2 activators and a KEAP1 inhibitor on an in vitro model of M1 and M2 macrophage polarization. The objective was to investigate whether these compounds could enhance antioxidative response. To evaluate this, key genes and proteins involved in antioxidative pathways were analyzed. Gene expression was assessed using quantitative real-time PCR (qPCR), and protein presence was determined through immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). The findings of this study indicate that stimulation of macrophage subgroups with the selected compounds promotes a shift towards anti-inflammatory and antioxidative response. / <p>Rektor tilldelade Leo Svahn stipendie Österby för <em>välartade obemedlade studier</em>.</p>

GONÇALVES, Fabrício Mota. Evapotranspiração e coeficientes de cultivo (KC) da cana-de-açúcar irrigada por gotejamento subsuperficial. 2010. 64 f. : Dissertação (mestrado) - Universidade Federal do Ceará, Centro de Ciências Agrárias, Departamento de Engenharia Agrícola, Programa de Pós-Graduação em Engenharia Agrícola, Fortaleza-CE, 2010. / Submitted by demia Maia (demiamlm@gmail.com) on 2016-06-28T16:59:16Z No. of bitstreams: 1 2010_dis_fmgonçalves.pdf: 3900094 bytes, checksum: 1ad79acf1432c0de09bcbdf52cb0f8c3 (MD5) / Approved for entry into archive by demia Maia (demiamlm@gmail.com) on 2016-06-28T16:59:48Z (GMT) No. of bitstreams: 1 2010_dis_fmgonçalves.pdf: 3900094 bytes, checksum: 1ad79acf1432c0de09bcbdf52cb0f8c3 (MD5) / Made available in DSpace on 2016-06-28T16:59:48Z (GMT). No. of bitstreams: 1 2010_dis_fmgonçalves.pdf: 3900094 bytes, checksum: 1ad79acf1432c0de09bcbdf52cb0f8c3 (MD5) Previous issue date: 2010 / Sugar cane is one of the crops with the highest level of water consumption, with a high evapotranspiration demand throughout most of its cycle. Knowledge of the sugar cane water demand, the time that irrigation should be applied, and how to irrigate the crop are becoming increasingly important for the sustainable development of irrigated sugar cane cultivation, especially in areas of low water availability, as it is the case in northea stern Brazil. The experiment was carried out at the Curu Experimental Field (property of the Embrapa Tropical Agroindustry), located in the Curu-Paraipaba Irrig ation Project, city of Paraipaba-CE (3 ° 29 '20''S, 39 ° 9' 45''W and elevation 30m), in order to determine the evapotrans piration and crop coefficients (Kc) of sugarcane (Saccharum L. officinarium), subsurface drip-irrigated. It was used the SP 6949 sugar cane variety, planted in a spacing of 1.8 m between double rows and 0.4 m between rows within the double row. As to t he irrigation, we used one lateral water line for each double row, buried at a depth of 0.15 m, w ith self-compensating drip emitters, with a flow rate of 1 L h-1, spaced 0.5 m on the water line. The crop was irrigated daily and there were three fertigations per week. The irrigation de pth was periodically adjusted, keeping the soil water potential between -8 kPa to -20 kPa. The crop evapotranspiration (ETc) was determined using a wei ghing lysimeter with a surface area of 2.25 m 2. The reference evapotranspiration (ETo) was estimated by the FAO Penman-Monteith method. The durations of the phenological stages of cane sugar were estimated through analysis of soil cover, with the use of digital images. Durations of 31, 49, 237 and 118 days were observed, respectively for initial, crop development, mid-season and late season stages. The yields achieved within and outside the lysimeter were respectively 144.4 and 108.8 t ha -1 . The total ETc observed during the cycle of the sugar cane was 1074.1 m m, with maximum values of 6.6 mm d-1 during the mid-season stage. Observed Kc values for initial, mid-season and late season stages were respectively 0.23, 1 .03 and 0.50. In the crop development stage, the relationship between Kc and the (crop) soil cover was represented with good accuracy by a negative quadratic model. / A cana-de-açúcar é uma das culturas com maior consumo de água, apresentando uma alta demanda evapotranspirativa ao longo da maior parte do seu ciclo. O conhecimento das necessidades hídricas da cana-de-açúcar, do momento de aplicação da água requerida pela mesma e a forma de aplicação torna-se cada vez mais importante para o desenvolvimento sustentável da sua produção irrigada, principalmente em regiões de pouca disponibilidade hídrica, como é o caso da região Nordeste do Brasil. O experimento foi conduzido no Campo Experimental do Curu, pertencente à Embrapa Agroindústria Tropical localizado no Perímetro Irrigado Curu-Paraipaba, município de Paraipaba-CE (3° 29’ 20’’ S, 39° 9’ 45’’ W e altitude de 30 m), com o objetivo de determinar a evapotranspiração e os coeficientes de cultivo (Kc) da cana-de-açúcar (Saccharum officinarium L.), irrigada por gotejamento subsuperficial. Utilizou-se a variedade de cana SP 6949, plantada no espaçamento de 1,8 m entre fileiras duplas e 0,4 m entre linhas dentro da fileira dupla. Na irrigação utilizou-se uma linha lateral para cada fileira dupla, enterrada na profundidade de 0,15 m, com gotejadores autocompensantes, com vazão de 1 L h-1, espaçados de 0,5 m na linha. A cultura foi irrigada com freqüência diária e foram realizadas três fertirrigações por semana. A lâmina de irrigação foi ajustada periodicamente, mantendo-se o potencial de água no solo entre -8 kPa e -20 kPa. A evapotranspiração da cultura (ETc) foi determinada utilizando-se um lisímetro de pesagem com área superficial de 2,25 m2. A evapotranspiração de referência (ETo) foi estimada pelo método FAO Penman-Monteith. As durações das fases fenológicas da cana-de-açúcar foram estimadas por meio da análise da cobertura do solo pela cultura, determinada com o uso de imagens digitais. Foram observadas durações de 31, 49, 237 e 118 dias, para as fases inicial, de desenvolvimento, intermediária e final, respectivamente. A produtividade alcançada dentro e fora do lisímetro foi de 144,4 e 108,8 t ha-1, respectivamente. A ETc total observada durante o ciclo da cana-de-açúcar foi de 1.074,1 mm, com valores máximos da ordem de 6,6 mm d-1 durante a fase intermediária. Foram observados valores de Kc iguais a 0,23, 1,03 e 0,50, para as fases inicial, intermediária e final, respectivamente. Na fase de desenvolvimento vegetativo a relação entre o Kc e a cobertura do solo pela cultura foi representada com bastante exatidão por um modelo quadrático negativo.