BACKGROUND: Long-term exposure to fine particulate matter (PM2.5) has been identified as a potential risk factor for developing type 2 diabetes mellitus (T2DM). Given the rising prevalence of T2DM and unhealthy concentrations of PM2.5 in China, our attention is brought to examining the association in this region of the world. Furthermore, rural China, although largely ignored, also finds itself suffering from increased risks of T2DM and high levels of PM2.5. OBJECTIVE: The goal of this study is to characterize the relationship between long-term exposure to PM2.5 and the risk of T2DM in rural China. We do so by confirming that greater long-term exposure to PM2.5 is associated with a higher risk of T2DM incidence, assessing the potential multiplicative and additive interactions with important covariates, and identifying constituents of PM2.5 that may be responsible for the effect PM2.5 on the increased incidence of T2DM. CONCLUSIONS: Greater long-term exposure to PM2.5 is associated with increased risk of developing T2DM in rural Deqing County, Zhejiang, China. Smoking status modifies the relationship between PM2.5 and T2DM incidence on a multiplicative scale. There is no synergism between smoking and PM2.5 in association with T2DM incidence. There is no conclusive evidence on which constituents of PM2.5 play greater roles in the adverse effects of PM2.5 on T2DM incidence.

Type IV pili (T4P) are long, thin, flexible surface appendages used by various bacteria for surface adhesion, cell-cell aggregation, DNA uptake, biofilm formation and motility. Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen, and uses T4P as a key virulence factor to infect immunocompromised individuals. Four subcomplexes make up a functional T4P system in P. aeruginosa and the role of the alignment subcomplex is to physically connect the outer membrane pore with the inner membrane motor, allowing for efficient extrusion of the pilus fibre from the cell. Two alignment subcomplex proteins, PilN and PilO, form heterodimers and are required for proper function of the system. These proteins may be able to transduce signals between various T4P components to indicate extension and/or retraction of the pilus fibre. This thesis focused on characterization of the interaction interfaces between PilN and PilO, and on understanding the dynamics required for proper function of the system. We show that although PilN and PilO make extensive interaction contacts throughout their lengths, single point substitutions at key residues can successfully disrupt the function of the T4P system. Crosslinking PilN and PilO as homo- or heterodimers can disrupt motility and surface piliation, indicating that interfaces between these proteins must be dynamic to allow proper T4P function. A high resolution X-ray crystal structure of PilO was solved and exhibits new structural features previously unidentified. This work furthers our understanding of the structures and regions of interaction between PilN and PilO, as well as defining a role for these proteins in extension and retraction. / Dissertation / Doctor of Philosophy (PhD) / Pseudomonas aeruginosa is an opportunistic bacterium, able to infect individuals with weakened immune systems. It attaches to and moves along surfaces using long, thin, sticky, retractable fibres known as type IV pili. Similar to a grappling gun, a functional type IV pilus system requires four subcomplexes working in unison to allow for the extension, adherence, and retraction of pilus fibres, which pulls the cell forward towards the point of attachment. Two key proteins, PilN and PilO, are bound to each other and allow for efficient extension and retraction of the pilus fibre. This study focused on characterization of the interactions of PilN and PilO, and on understanding whether dynamic rearrangements of the interfaces between these proteins is required for proper function of the system. We show that although these proteins have extensive interaction interfaces, single residue substitutions in either of them can disrupt the ability of the bacteria to properly extend and/or retract their pili. This work furthers our understanding of the structures and regions of interaction between PilN and PilO, providing information that might allow disruption of these interfaces to block bacterial attachment or motility, both of which are important for infection.

Type IVa pili (T4aP) are long, retractile, filamentous, surface appendages involved in cellular surface adhesion, biofilm formation, DNA uptake, and a unique form of motility called ‘twitching’. They are a critical virulence factor in a number of bacteria, including the opportunistic pathogen Pseudomonas aeruginosa, a major cause of hospital-acquired infections. T4aP function is controlled by a number of different regulatory proteins and systems. A putative chemosensory system termed ‘Chp’, controls levels of the second messenger molecule cyclic adenosine monophosphate (cAMP). cAMP works with a cAMP receptor protein called Vfr to control expression of ~200 virulence genes, including those that are required to make T4aP. cAMP levels are regulated by proteins outside the Chp system, including the bitopic inner membrane protein, FimV. This study examines the role of the Chp system and FimV in T4aP regulation. Both proteins are required for regulation of cAMP levels, while the Chp system also has a cAMP-independent role in regulating twitching. FimV has been shown to regulate cAMP levels, possibly connecting to the Chp system through a scaffold protein, FimL. We present the structure of a conserved cytoplasmic region of FimV, and show that this region is required for connecting FimV to the Chp system. We also characterize the cAMP-independent role of FimV, confirming that it is distinct from that of the Chp system, and is involved in localizing T4P regulatory proteins. We also provide evidence that the cAMP-independent role of the Chp system is to mediate the balance between T4P extension and retraction, possibly through denoting the ‘front’ of a motile cell. Together, these data help to resolve the cAMP-independent and –dependent pathways controlling twitching motility. / Thesis / Doctor of Philosophy (PhD) / Pseudomonas aeruginosa is a bacterium that causes infection in people with weakened immune systems. One key factor it uses to cause infection is the type IVa pilus (T4aP), a filamentous appendage displayed on the cell surface. T4aP can repeatedly extend and retract, and are involved in attachment to host cells, and movement along surfaces. When T4aP cannot extend or retract, the bacteria cannot cause infection. Many proteins work together to control T4aP function – this study focuses on two of them. They have one overlapping function, controlling levels of a signalling molecule needed to make T4aP. We also show that they have a second, non-overlapping function. One is involved in controlling the extension/retraction balance, possibly by marking the front of a cell, while the other may localize pilus-related proteins within a cell. This work helps us understand how P. aeruginosa makes T4aP, and provides information helpful to understanding control of virulence.

Aims: to test the hypothesis that peripheral blood neutrophils (PMN) exhibit delayed spontaneous apoptosis in individuals with type 2 Diabetes, and that the delay is further exacerbated in individuals who co-express chronic periodontitis. Materials and methods: 73 individuals were enrolled, including those with type 2 diabetes (T2DM) (n=16), chronic periodontitis (CP) (n=15), diabetics with chronic periodontitis (T2DM+CP) (n=21) and healthy volunteers (n=21). PMN apoptosis was determined by flow cytometry using TUNEL and Annexin V assays. Caspase 3, 8 and 9 activity was measured by colorimetric assay. PMN surface death receptor quantification was performed by flow cytometry staining with fluorescence conjugated anti-CD120a (TNFR1) and anti- CD95 (FasR) antibody. Inflammatory biomarker analyses of serum samples were performed using multiplexed sandwich immunoassays. Results: In healthy volunteers, individuals with T2DM, CP and T2DM+CP, spontaneous PMN apoptosis observed at 12 hours reached 85.3% ± 3.1, 67.3% ± 3.9, 62.9% ± 3.5 and 62.5% ± 5.4, respectively (p<0.05 ). Caspase-3 activity was significantly reduced in individuals with T2DM and T2DM+CP (p<0.05), when compared to healthy volunteers. Caspase-8 activity was also significantly decreased in CP and T2DM+CP (p<0.05), associated with reduced cell surface Fas receptor, TNF receptors and Fas ligand serum levels. Glucose alone was not observed to effect PMN apoptosis; concurrent incubation with the RAGE agonist S-100B induced a significant PMN apoptosis (p<0.05). Conclusion: These data support the premise that the inhibition of PMN apoptosis in individuals with T2DM occurs through an AGE/RAGE ligand/receptor mediated interaction.

The Norrbotten region is an important Swedish mining district with occurrence of several economic deposits and sub-economic deposits of apatite iron ores (Kiruna Type) and epigenetic Cu-Au ores. The apatite iron ores include the large Malmberget deposit mined by LKAB company as one of their world class underground mines. The Malmberget ores are hosted by a Paleoproterozoic unit of metavolcanics and metasedimentary rocks intruded by multiple plutonic rocks varying in composition. The rocks at Malmberget are overprinted by intense widespread hydrothermal alteration, metamorphism and deformation. The Malmberget iron deposit is thought to originally be one continuous lens that segmented into more than 20 different orebodies during the regional metamorphism and deformation. The Malmberget deposit is characterized by different orebodies that shows different textures and chemical variations. The iron ores at Malmberget are mainly consisting of magnetite and hematite.   Apatite iron ores of the Kiruna type have raised divergent opinions regarding whether this type of deposits are magmatic or hydrothermal in origin. However, trace element analysis have been used for studies that yield information about ore-forming fluids and mineralizing processes. This paper aims at understanding the vanadium behaviour and distribution in the Malmberget ores as well as studying textural and mineralogical control of vanadium in the iron ores. Learnings from this paper aids in understanding the controls and distribution of vanadium and increasing knowledge regarding genetic aspects of the Malmberget deposit. To achieve this, detailed core logging, optical microscopy, lithogeochemistry and scanning electron microprobe analyses were utilized to figure out why the vanadium content is high in some places and low in other parts of the deposit.  Textural data of both magnetite and hematite ores show that the Malmberget ores can be characterized as massive ore and breccia type. The ores in the western part of the deposit are dominated by metamorphic and oxidation textures, including martitisation textures and triple junction textures. The ores in the eastern part are mainly massive magnetite textures with apatite and amphibole as the main gauge minerals. Metamorphic recrystallization and oxidation of the ores resulted in vanadium redistribution and chemical changes of both hematite and magnetite. Vanadium is high in both magnetite and hematite ore and low in the silicate host rocks. The eastern ore bodies of the deposit are found to be higher in vanadium content compared to those on the western side. Vanadium is high in magnetite ore sections but in magnetite-hematite grain pairs vanadium is redistributed from the magnetite grain to the adjacent hematite grain during metamorphic oxidation and recrystallization of magnetite. The results from this project suggest that a better understanding of what controls the distribution of vanadium in the ores needs more investigations regarding element partition under different geochemical conditions. There are also uncertainties regarding the initial source of vanadium and its primary distribution in different minerals and ore types and later redistributions. The origin of hematite in the ores and the stratigraphic position of the ores are other aspects that needs further studies to get a deeper understanding of the behaviour of vanadium in the Malmberget deposit.

No description available.

No description available.

No description available.

No description available.

No description available.