This thesis examined neurotoxic effects of nicotine exposure during a defined critical period of neonatal brain development in mice. In our environment there are numerous hazardous contaminants that an individual can be exposed to during its entire lifetime. In many mammalian species the neonatal period is characterised by a rapid development of the brain. The present studies have identified a defined critical period during the neonatal brain development in mice, where exposure to low doses of nicotine causes permanent disturbances in the cholinergic nicotinic receptors and altered behaviour response to nicotine at adult age. This adult reaction to nicotine, a hypoactive response, was the opposite of that observed in control animals and animals exposed to nicotine before or after this period. Animals showing a hypoactive response to nicotine lacked nicotinic low affinity binding sites in the cerebral cortex. Furthermore, neonatal exposure to nicotine affected learning and memory in adult animals, an effect that was time-dependent. This thesis also showed that neonatal exposure to nicotine increased adult susceptibility to a repeated exposure of nicotine, manifested as an even more pronounced effect in spontaneous behaviour after challenging doses of nicotine. In these animals the nicotinic receptors in the cerebral cortex, assayed by a-bungarotoxin, was decreased. Neonatal exposure to nicotine was also shown to increase adult susceptibility to the organophosphate paraoxon, a known cholinergic agent, and to the brominated flame retardant 2,2´,4,4´,5-pentabromodiphenyl ether, a novel environmental agent, at adult age. This was seen at doses that did not affect behaviour in control animals, and was manifested as deranged spontaneous behaviour and reduced habituation, aberrations that also worsened with age. The results indicate that differences in adult susceptibility to environmental pollutants are not necessarily an inherited condition. Rather they may well be acquired by low dose exposure to toxic agents during early life.

IIn the first study, we investigated the functional implications of prolonged TLR signalling on IFN-γ mediated killing of mycobacteria by murine macrophages in vitro. TLR2, but not TLR4 ligation interfered with IFN-γ mediated killing of mycobacteria in macrophages. In terms of mechanisms, neither TNF nor nitric oxide (NO) production was significantly affected, and the refractoriness induced could be reversed with increasing amounts of IFN-γ In the second study, we aimed to identify immunological markers of diagnostic importance in both the respiratory tract and serum during pulmonary mycobacterial infection in mice. We found that increased levels of immunological markers in the respiratory tract, but not serum, correlated better with active mycobacterial infection in the lungs, suggesting that the immune response in the respiratory tract is more reflective of the infection status and pathology than the systemic response. Finally, we investigated the level and nature of immune responses to pulmonary mycobacterial infection in BALB/c and C57BL/6 mice, two mouse strains known to exhibit different susceptibilities to infection with several intracellular pathogens, including mycobacteria. We showed that increased susceptibility of BALB/c mice to early mycobacterial infection was associated with reduced Th1 immune responses, and increased sTNFR secretion in the lung. Moreover, BALB/c mice recruited fewer monocytes/macrophages to the lung, and although IFN-γ stimulation of infected bone marrow derived macrophages in both mouse strains resulted in induction of antimycobacterial activity, BALB/c mice had a reduced capacity to kill ingested bacteria. The work presented in this thesis provide further insight into the mechanisms involved in the host-pathogen interaction; from persistence, to the immunological processes induced by the pathogen, to susceptibility of the host to infection.

Systemic Lupus Erythematosus (SLE) is a chronic multi-organ autoimmune disease considered a prototype for autoantibody and immune complex-mediated tissue injury. Although autoantibodies against a wide diversity of self-antigens are characteristically found in this disease, an important hallmark is the presence of autoantibodies to nuclear antigens. Despite this common clinical feature, individual patients vary widely in the organ systems afflicted, disease severity, disease course, and response to treatment. These characteristics make clinical management of SLE challenging and highlight the need for effective and less toxic therapeutic interventions. Susceptibility to lupus has been shown in both human studies and mouse models to be dependent on genetic predisposition. Therefore, it is likely that knowledge of the genetic basis of SLE will be required before full understanding of SLE pathogenesis can be achieved. In this thesis, studies to define the genetic basis of lupus in an induced and two spontaneous models of the disease are presented. These studies encompass mapping, characterization of interval congenic mice, and cloning of the Lmb3 locus gene. In the first study, a genomewide mapping study was performed to define the genetic basis for resistance of the DBA/2 mice to mercury-induced autoimmunity. On chromosome 1, a single quantitative trait was linked with resistance to HgIA. These results linked the locus Hmr1 to a late stage of lupus with GN. Interval congenic mice are important tools to define and characterize the roles of different loci in lupus-like diseases. The second paper identifies the effect of NZB and NZW Lbw2 alleles on lupus susceptibility by using BWF1 mice with none, one or two copies of the lupus-predisposing NZB.Lbw2 locus. The lack of the NZB locus significantly reduced mortality, GN and B cell activation. IgM anti-chromatin levels in genome-wide mapping was linked only to Lmb2 and none of the known B cell hyperactivity-promoting genes were present in this location, which might indicate a novel B cell activation gene. The third study used reciprocal single locus interval-specific congenic mice to characterize the contribution of Lmb1-4 on the MRL-Faslpr and B6-Faslpr backgrounds. The Lmb3 locus on chromosome 7 was found to have the most prominent phenotype with clear effects on lymphoproliferation, GN and mortality. In the fourth paper the Lmb3 was cloned and shown to be a spontaneous nonsense mutation in the Coro1a gene that encodes an actin-binding and -regulatory protein. Upon further characterization, this genetic alteration was discovered to be a new lupus suppressing mutation that reduced T cell migration, activation, and survival. Our findings highlight the complexity of the genetics of lupus, and further suggest that genes involved in controlling the actin cytoskeleton might be potential targets for autoimmune therapeutics.

No description available.

Background Customer satisfaction is important for clinical microbiology laboratories and the most important service aspect is the reliability of responses. One important indicator of the quality of care is turnaround time for a sample referred to a laboratory. Aim This study describes and evaluates an improvement of the blood culture process and evaluates the staff’s experiences of the changes brought by the improvement project. Methods The blood culture process during evenings and nights was re-designed in a cooperation project between the laboratories of clinical microbiology and clinical chemistry in a mid-size Swedish county council. Typing with matrix-assisted laser desorption/ionization time of flight (MALDI ToF) and rapid antibiotic susceptibility testing were also introduced. To describe staff experi-ences semi-structured interviews were performed with twelve of the staff involved. Results The time from sampling to susceptibility testing and typing, for patients with cefotaxime resistant enterobacteriaceae, was before the improvement project on average 55 hours compared to 43 hours after closure of the project. In the qualitative content analysis four categories were found which represented the experience of the staff: patient focus, changed knowledge, cooperation and driving forces. Discussion The study of the implementation of the improvement showed that laboratory staff could handle the change well. The change from traditional biochemical typing, used for over 50 years, to MALDI ToF is indeed a paradigm shift. Nevertheless, nobody was disappointed over the fact that some of the fundamental previous microbiological laboratory work routines were laid to rest.

The increasing infection of Cryptococcus species and Tricosporon asahii emerged in clinical patients who were immunocompromised. They usually induce lung, skin, brain and systemic infection. Morbidity and mortality of immunocompromised patients are higher than normal healthy people. Cryptococcus neoformans var. grubii ¡]serotype A¡^ infections were reported in clinical cases predominantly and they were isolated from birds¡¦ droppings in large amount. Cryptococcus neoformans var. gattii ¡]serotype B, C¡^ had a natural life in plants, especially Eucalypticus trees. Isolations from other trees were reported increasingly in the tropical and subtropical areas. Comparing to Cryptococcus species, Tricosporon asahii is the normal mycoses of soil. In this study, we performed an environmental investigation concerning Cryptococcus species and Tricosporon asahii in Southern Taiwan. 120 droppings of racing pigeons and 114 samples from Eucalypticus trees were obtained. The results revealed that 30 Cryptococcus neoformans were isolated from racing pigeons¡¦ droppings ¡]25%¡^, as well as 4 Cryptococcus laurentii ¡]3.3%¡^ and 2 Cryptococcus albidus ¡]1.7%¡^. In addition, 25 Tricosporon asahii ( 20.8% ) were isolated from droppings of racing pigeons. But, none of Cryptococcus species or Tricosporon asahii is isolated from Eucalypticus trees ¡]0%¡^. All of Cryptococcus neoformans isolated from pigeons¡¦ droppings were var. grubii ¡]serotype A¡^ and their drug susceptibility tests showed sensitive to Amphotericin B ¡]minimal inhibitory concentration ¡Ø0.25£gg/ml¡^ and Fluconazole ¡]minimal inhibitory concentration 2£gg/ml¡^ and Flucytosine ¡]minimal inhibitory concentration ¡Ø1£gg/ml¡^. To sum up, both Cryptococcus species and Tricosporon asahii were isolated from droppings of racing pigeons in our study, especially Tricosporon asahii in large amount. Opportunistic infection caused by these species should be given more attention to racing pigeons which have close contact with human . Intensive investigation and surveillance should be carried out in the future to provide an information for the control and prevention of diseases.

Tumor susceptibility gene 101¡]TSG101¡^encodes an inactive ubiquitin conjugating E2 enzyme implicated in regulation of protein sorting, vesicular trafficking, transcription activation of nuclear receptor, cell growth and differentiation. Previous studies showed that TSG101 can be mono- or poly- ubiquitinated, which is relevant to its functional status. There are seven Lysine (K) sites, K6, K11, K27, K29, K33, K48 and K63, on ubiquitin (Ub). Polyubiquitination using different Ub K sites confers differential function for protein degradation, DNA damage repair, endocytosis and protein sorting. AIP4 E3 ubiquitin ligase modifies its substrates involved in erythroid and lymphoid lineage differentiation and the associated immune responses. Mutation in AIP4 gene resolves in multisystemic autoimmune disease. TSG101 was recently shown to be a molecular checkpoint for T cell receptor downregulation. Here we investigate the ubiqutination status of TSG101. The ubiquitin-conjugated protein in lysate of cells co-transfected with pHA-TSG101 and His-tagged wild type Ub or each K site mutant ubiquitin expression plasmids was purified on nickel beads and then subjected to western blotting using antibodies against HA-TSG101 or His-tag. The results showed that K series mutant had differential effect on the steady-state of HA-TSG101. Proteasome inhibitor could alleviate its degradation especially in the K63 ubiquitin expression group, implying K63 ubiquitination E3 ligase is critical in maintaining HA-TSG101 level. Our coimmunoprecipitation result demonstrated the interaction between AIP4 and HA-TSG101, implying that TSG101 might be a substrate for AIP4. The ectopic overexpression of AIP4 increased the amount of HA-TSG101 in an E3 ligase activity depended manner. Taken together, these results indicated that AIP4 activity mediating Ub K63 modification might be critical for regulating cellular TSG101 protein level. Further experiment should clarify this issue.

Mass movement can be activated by earthquakes, rapid snowmelt, or intense rainstorms in conjunction with gravity. Whereas mass movement plays a major role in the evolution of a hillslope by modifying slope morphology and transporting material from the slope to the valley, it is also a potential natural hazard. Determining the morphology of the mountain slopes and the relationships of frequency and magnitude of landslides are fundamental to understanding the role of landslides in the study of landscape evolution, and hazard assessment. Characteristics of the geomorphic zones in a periglacial landscape were evaluated by plotting local slopes and the drainage areas in Paonia-McClure Pass area of western Colorado. The study suggested that the steepness and concavity of mountain slopes and stream channels in the study area are related by an exponential equation. Seven hundred and thirty five shallow landslides (<160,000 m2) from the same study area were mapped to determine the frequency-magnitude relationships of shallow landslides and to develop an optimum model of mapping susceptibility to landslides. This study suggests that the frequency-magnitude of the landslides in Paonia-McClure Pass area are related by a double pareto equation with values α= 1.1, and β = 1.9 for the exponents. The total area of landslides is 4.8x10⁶ m² and the total volume of the landslides is 1.4x10⁷ m³. The areas (A) and the volumes (V) of landslides are related by V = 0.0254xA^1.45. The frequency-magnitude analysis shows that landslides with areas ranging in size from 1,600 m2 - 20,000 m2 are the most hazardous landslides in the study area. These landslides are the most frequent and also do a significant amount of geomorphic work. Three quantitative approaches: weight of evidence; fuzzy logic; and logistic regression; were employed to develop models of mapping landslides in western Colorado. The weight of evidence approach predicted 78 percent of the observed landslides, the fuzzy-logic approach also predicted 78 percent of the observed landslides, and the logistic regression approach predicted 86 percent of the observed landslides.

With the enormously developing of the wireless communication technology, the electromagnetic environment exposing to the electrical devices is becoming more and more complex. Besides, the trends of designing high-speed digital computer systems are toward fast edge rates, high clock frequencies, and low voltage levels. The electromagnetic susceptibility (EMS) or immunity of the high-speed circuit has become an important issue today apparently. In this thesis, we will firstly establish the measurement environment and calibration technology for numerical validation. Then we employ the three-dimension finite-differential time-domain (3D-FDTD) numerical method compared to the finite element method (FEM) to simulate the EMS behavior of the power delivery network (PDN) and traces of the printed circuit boards (PCB). In addition to several types of layout of the traces studied in this thesis, we also explain the mechanism and phenomenon of the EMS of the power/ground planes of the PCB. Besides the EMS behavior research of the traditional solutions to suppress the power noise, we propose an electromagnetic bandgap structure (EBG) which has the broadband suppression of the power noise and is validated to be effective to improve the EMS problems. Finally, we also propose a novel concept to increase the signal integrity (SI) by shielding design.

The purpose of this study is to evaluate and to compare the results of bivariate statistical analysis conducted with three different data sets in Geographical Information Systems (GIS) based landslide susceptibility mapping applied to the Devrek region. The data sets are created from the seed cells of crowns and flanks, only crowns, and only flanks of the landslides by using 10 different parameters of the study area. To increase the data dependency of the analysis, all parameter maps are classified into equal frequency classes based directly on the percentile divisions of each seed cells data set. The resultant maps of the landslide susceptibility analysis indicate that all data sets produce acceptable results. In each seed cell data set analysis, elevation, lithology, slope, aspect and drainage density parameters are found to be the most contributing factors in landslide occurrences. The results of the three data sets are compared by Seed Cell Area Index (SCAI). This comparison shows that the crowns data set produces the most accurate and successful landslide susceptibility map of the study area.