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The Surface Dust Analyser (SUDA) is a mass spectrometer onboard the Europa Clipper mission for investigating the surface composition of the Galilean moon Europa. Atmosphereless planetary moons such as the Galilean satellites are wrapped into a ballistic dust exosphere populated by tiny samples from the moon’s surface produced by impacts of fast micrometeoroids. SUDA will measure the composition of such surface ejecta during close flybys of Europa to obtain key chemical signatures for revealing the satellite’s composition such as organic molecules and salts, history, and geological evolution. Because of their ballistic orbits, detected ejecta can be traced back to the surface with a spatial resolution roughly equal to the instantaneous altitude of the spacecraft. SUDA is a Time-Of-Flight (TOF), reflectron-type impact mass spectrometer, optimized for a high mass resolution which only weakly depends on the impact location. The instrument will measure the mass, speed, charge, elemental, molecular, and isotopic composition of impacting grains. The instrument’s small size of 268 mm × 250 mm × 171 mm , radiation-hard design, and rather large sensitive area of 220 cm 2 matches well the challenging demands of the Clipper mission.

The Nano-Dust Analyzer (NDA) instrument is developed for the detection and compositional analysis of nanometer-sized dust particles originating near the Sun, and delivered near Earth’s orbit by radiation pressure and electromagnetic forces. These particles report on processes occurring close to the Sun. This thesis investigates the basic dynamical processes and the results of the numerical calculations are then used to design and optimize the NDA, a linear time-of-flight mass analyzer. The challenge of needing high sensitivity of detection while pointed close to Sun’s direction is solved by optimizing the instrument’s field-of-view, pointing requirements, and designing an internal baffle system to suppress the effects of solar-ultraviolet radiation. Little is known about the origin, distribution and fate of dust particles in the inner Solar System. The interplanetary dust complex is fed mostly by comets and asteroids. The interplanetary dust particles are transported towards the Sun (on timescales of ~ thousands of years) where they undergo multiple processes: most are destroyed by the heat of the Sun or sputtering by solar wind particles, while a small fraction is expelled out of the Solar System. Grinding from mutual collisions alters their size distribution, which intensifies closer to the Sun, where their density increases. These particles influence the solar wind plasma, being one of the sources of inner source pickup ions, or mass loading the expanding solar wind. The importance of these effects is yet to be fully understood. The population of particles expelled from the Solar System include submicron-sized dust particles known as ?-meteoroids, which are accelerated by solar radiation pressure. Nanometer-sized particles also belong to this population and are picked up and accelerated to high velocities by the solar wind. There is likely a wealth of information in their mass distribution, composition and dynamical properties, including their temporal and spatial flux variations, which is influenced by their interaction with the solar wind. Past missions have identified and partially-characterized particles originating from the inner Solar System. This thesis lays the foundations for providing measurements to resolve outstanding science questions by presenting a concept for their detection and a basic design for a capable instrument.

Serum amyloid A (SAA) increases in response to acute inflammatory stimuli and is modestly and chronically elevated in obesity. SAA3, an inducible form of SAA, is highly expressed in adipose tissue in obese mice where it promotes monocyte chemotaxis, providing a mechanism for the macrophage accumulation that occurs with adipose tissue expansion in obesity. Humans do not express functional SAA3 protein, but instead express SAA1 and SAA2 in hepatic as well as extrahepatic tissues, making it difficult to distinguish between liver and adipose tissue-specific SAA effects. SAA3 does not circulate in plasma, but may exert local effects that impact systemic inflammation. We tested the hypothesis that SAA3 contributes to chronic systemic inflammation and adipose tissue macrophage accumulation in obesity using mice deficient for Saa3 (Saa3(-/-)). Mice were rendered obese by feeding a pro-inflammatory high fat, high sucrose diet with added cholesterol (HFHSC). Both male and female Saa3(-/-) mice gained less weight on the HFHSC diet compared to Saa3(+/+) littermate controls, with no differences in body composition or resting metabolism. Female Saa3(-/-) mice, but not males, had reduced HFHSC diet-induced adipose tissue inflammation and macrophage content. Both male and female Saa3(-/-) mice had reduced liver Saa1 and Saa2 expression in association with reduced plasma SAA. Additionally, female Saa3(-/-) mice, but not males, showed improved plasma cholesterol, triglycerides, and lipoprotein profiles, with no changes in glucose metabolism. Taken together, these results suggest that the absence of Saa3 attenuates liver-specific SAA (i.e., SAA1/2) secretion into plasma and blunts weight gain induced by an obesogenic diet. Furthermore, adipose tissue-specific inflammation and macrophage accumulation are attenuated in female Saa3(-/-) mice, suggesting a novel sexually dimorphic role for this protein. These results also suggest that Saa3 influences liver-specific SAA1/2 expression, and that SAA3 could play a larger role in the acute phase response than previously thought.

Widely used as a weight loss supplement, trans-10,cis-12 conjugated linoleic acid (10,12 CLA) promotes fat loss in obese mice and humans, but has also been associated with insulin resistance. We therefore sought to directly compare weight loss by 10,12 CLA versus caloric restriction (CR, 15-25%), an acceptable healthy method of weight loss, to determine how 10,12 CLA-mediated weight loss fails to improve glucose metabolism. Obese mice with characteristics of human metabolic syndrome were either supplemented with 10,12 CLA or subjected to CR to promote weight loss. Metabolic endpoints such as energy expenditure, glucose and insulin tolerance testing, and trunk fat distribution were measured. By design, 10,12 CLA and CR caused equivalent weight loss, with greater fat loss by 10,12 CLA accompanied by increased energy expenditure, reduced respiratory quotient, increased fat oxidation, accumulation of alternatively activated macrophages, and browning of subcutaneous white adipose tissue (WAT). Moreover, 10,12 CLA-supplemented mice better defended their body temperature against a cold challenge. However, 10,12 CLA concurrently induced the detrimental loss of subcutaneous WAT without reducing visceral WAT, promoted reduced plasma and WAT adipokine levels, worsened hepatic steatosis, and failed to improve glucose metabolism. Obese mice undergoing CR were protected from subcutaneous-specific fat loss, had improved hepatic steatosis, and subsequently showed the expected improvements in WAT adipokines, glucose metabolism and WAT inflammation. These results suggest that 10,12 CLA mediates the preferential loss of subcutaneous fat that likely contributes to hepatic steatosis and maintained insulin resistance, despite significant weight loss and WAT browning in mice. Collectively, we have shown that weight loss due to 10,12 CLA supplementation or CR results in dramatically different metabolic phenotypes, with the latter promoting a healthier form of weight loss.

Adipose tissue inflammation and specifically, pro-inflammatory macrophages are believed to contribute to insulin resistance (IR) in obesity in humans and animal models. Recent studies have invoked T cells in the recruitment of pro-inflammatory macrophages and the development of IR. To test the role of the T cell response in adipose tissue of mice fed an obesogenic diet, we used two agents (CTLA-4 Ig and anti-CD40L antibody) that block co-stimulation, which is essential for full T cell activation. C57BL/6 mice were fed an obesogenic diet for 16 weeks, and concomitantly either treated with CTLA-4 Ig, anti-CD40L antibody or an IgG control (300 µg/week). The treatments altered the immune cell composition of adipose tissue in obese mice. Treated mice demonstrated a marked reduction in pro-inflammatory adipose tissue macrophages and activated CD8+ T cells. Mice treated with anti-CD40L exhibited reduced weight gain, which was accompanied by a trend toward improved IR. CTLA-4 Ig treatment, however, was not associated with improved IR. These data suggest that the presence of pro-inflammatory T cells and macrophages can be altered with co-stimulatory inhibitors, but may not be a significant contributor to the whole body IR phenotype.

Obesity is a chronic inflammatory state characterized by altered levels of adipose tissue immune cell populations. Natural killer T (NKT) cells are CD1d restricted lymphocyte subsets that recognize lipid antigens whose level decreases in obese adipose tissue. However, studies in mice with deficiency or increased levels of NKT cells have yielded contradictory results, so the exact role of these cells in obesity and adipose tissue inflammation is not yet established. We previously showed that Ldlr−/− mice with excess invariant NKT (iNKT) cells demonstrate significant weight gain, adiposity, metabolic abnormalities, and atherosclerosis. The current study evaluates the effects of NKT cell deficiency on obesity, associated metabolic changes, and atherosclerosis in Jα18−/−Ldlr−/− (lacking iNKT cells) and Cd1d−/−Ldlr−/− (lacking invariant and type II NKT cells) mice, and control mice were fed an obesogenic diet (high fat, sucrose, cholesterol) for 16 weeks. Contrary to expectations, Ja18−/−Ldlr−/− mice gained significantly more weight than Ldlr−/− or Cd1d−/−Ldlr−/− mice, developed hypertriglyceridemia, and had worsened adipose tissue inflammation. All the mice developed insulin resistance and hepatic triglyceride accumulation. Ja18−/−Ldlr−/− mice also had increased atherosclerotic lesion area. Our findings suggest that iNKT cells exacerbates the metabolic, inflammatory, and atherosclerotic features of diet-induced obesity. Further work is required to unravel the paradox of an apparently similar effect of iNKT cell surplus and depletion on obesity.

BackgroundInsomnia is a well-recognized co-morbid condition in veterans with post-traumatic stress disorder (PTSD) with negative personal and social consequences. Cognitive behavioral therapy (CBT) is considered an efficacious treatment, yet little attention has been devoted to treatment response in this population. The aim of this study was to identify factors that may predict clinical response to CBT for insomnia (CBT-I) in veterans with PTSD.MethodsA retrospective chart review of 136 veterans with PTSD-related insomnia was conducted. Epworth Sleepiness Score (ESS), PTSD Checklist (PCL), and Insomnia Severity Index (ISI) were assessed at baseline. We converted prescribed antidepressant and hypnotic dosages before and after CBT-I to dose equivalent of fluoxetine diazepam, respectively. A 6-point reduction or greater in ISI scores at 6-month follow-up visit was defined as CBT-I responsiveness.ResultsCBT-I responsiveness was observed in 47% of veterans with PTSD. Seventy-seven percent completed treatment. Lack of perceived benefit was the most given reason for failure to return for follow-up. In contrast to hypnotics, antidepressants usage decreased in those who had experienced benefit from CBT-I (p = 0.001). Younger age, non-white race, and use of hypnotics prior to behavioral therapy were independently associated with lack of response to CBT-I.ConclusionsWhile CBT-I ameliorates insomnia in veterans with PTSD, the use of hypnotics prior to instituting behavioral therapy may negatively affect the response rate to CBT-I. Future studies should examine whether racial and cultural influences on the generation of insomnia in veterans with PTSD affects the response to CBT-I.

The dietary fatty acid 10,12 conjugated linoleic acid (10,12 CLA) promotes weight loss by increasing fat oxidation, but its effects on atherosclerosis are less clear. We recently showed that weight loss induced by 10,12 CLA in an atherosclerosis-susceptible mouse model with characteristics similar to human metabolic syndrome is accompanied by accumulation of alternatively activated macrophages within subcutaneous adipose tissue. The objective of this study was to evaluate whether 10,12 CLA-mediated weight loss was associated with an atheroprotective phenotype. Male low-density lipoprotein receptor deficient (Ldlr−/−) mice were made obese with 12 weeks of a high-fat, high-sucrose diet feeding (HFHS: 36% fat, 36% sucrose, 0.15% added cholesterol), then either continued on the HFHS diet with or without caloric restriction (CR), or switched to a diet with 1% of the lard replaced by either 9,11 CLA or 10,12 CLA for 8 weeks. Atherosclerosis and lipid levels were quantified at sacrifice. Weight loss in mice following 10,12 CLA supplementation or CR as a weight-matched control group had improved cholesterol and triglyceride levels, yet only the 10,12 CLA-treated mice had improved en face and aortic sinus atherosclerosis. 10,12 CLA-supplemented mice had increased lesion macrophage content, with enrichment of surrounding perivascular adipose tissue (PVAT) alternative macrophages, which may contribute to the anti-atherosclerotic effect of 10,12 CLA.

Traumatic brain injury causes a reduction in cerebral blood flow, which may cause additional damage to the brain. The purpose of this study was to examine the role of nitric oxide produced by endothelial nitric oxide synthase (eNOS) in these vascular effects of trauma. To accomplish this, cerebral hemodynamics were monitored in mice deficient in eNOS and wild-type control mice that underwent lateral controlled cortical impact injury followed by administration of either L-arginine, 300 mg/kg, or saline at 5 min after the impact injury. The eNOS deficient mice had a greater reduction in laser Doppler flow (LDF) in the contused brain tissue at the impact site after injury, despite maintaining a higher blood pressure. L-Arginine administration increased LDF post-injury only in the wild-type mice. L-Arginine administration also resulted in a reduction in contusion volume, from 2.4 ± 1.5 to 1.1 ± 1.2 mm3 in wild-type mice. Contusion volume in the eNOS deficient mice was not significantly altered by L-arginine administration. These differences in cerebral hemodynamics between the eNOS-deficient and the wild-type mice suggest an important role for nitric oxide produced by eNOS in the preservation of cerebral blood flow in contused brain following traumatic injury, and in the improvement in cerebral blood flow with L-arginine administration.