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Retinal neurodegenerative diseases including age-related macular degeneration(AMD), retinitis pigmentosa (RP), diabetic retinopathy (DR) and glaucoma are characterized by irreversible vision loss and currently have very limited therapies. Evidence has suggested the immune profile and inflammatory etiology in patients with retinal neurodegenerative diseases. Microglial activation is known to play an important role in neuroinflammation and neurodegeneration. However, there is a debate on whether microglial activation is the primary cause or a consequence of retinal neurodegeneration. It is also unclear why and how active microglia damage neurons since they are the main innate immune cells and their physiological role is to protect the neuroretina. Microglial activation is regulated by neurons. The chemokine CX3C motif receptor 1 (CX3CR1) is expressed exclusively by microglia in the central nerves system (CNS) and the retina; whereas the ligand, chemokine C-X3-C motif ligand 1 (CX3CL1) is expressed by neurons. The interaction between CX3CL1 and CX3CR1 is an important mechanism to avoid uncontrolled microglial activation. Microglia can be activated by inflammatory cytokines through the JAK/STAT pathway of cytokine receptors. Suppressor of cytokine signalling 3 (SOCS3) negatively regulates the JAK/STAT pathway. In this study, a mouse strain with the deletion of two inhibitory genes (CX3CR1 and SOCS3) in myeloid cells was created (named LysMCreSOCS3fl/flCX3CR1GFP/GFP, abbreviated as DKO in this thesis). The mice age dependently developed microglial activation and retinal neuronal degeneration. Clinical examinations in young (3-5 months) and aged (10-12 months) wild-type(WT) control, LysMCre-SOCS3fl/fl, CX3CR1GFP/GFP and DKO mice showed that cluster of GFP signals and fundus abnormalities in aged DKO retina but not in retinas from other ages or genotypes. Immunohistochemistry showed several alterations in aged DKO retina: 1) Uncontrolled microglial activation supported by increased microglial cell number in all layers, altered distribution and lectin expression; 2) Perturbed multiple retinal neurons including photoreceptors and bipolar cells and 3) Distorted RPE morphology (Chapter 3). To understand the mechanisms of active microglia-mediated retinal neuronal and RPE damage in the DKO mice, I investigated in Chapter 4 the phenotype and function of microglia from SOCS3fl/fl and DKO mice. The DKO microglia were found to have following properties: 1) Enhanced phagocytic activity; 2) Elevated mRNA expression of pro-inflammatory cytokines such as TNFα; 3) Upregulated cytokine secretion in basal condition and in response to diverse stimuli and 4) DKO microglia aggravated the mortality rate of cone photoreceptors in retinal organoid culture. These data revealed that DKO microglia possessed stronger phagocyticpotential and cytotoxic ability, exacerbating photoreceptor death after differentstimuli. To prove the retinal neuronal degeneration is primarily due to uncontrolled microglial activation, I used minocycline to control microglia activation in our LysMCre-SOCS3fl/flCX3CR1GFP/GFP mice at the age of 5 months (before the onset of retinal neuronal degeneration) for 3 consecutive months in Chapter 5. The treatment significantly supressed microglial activation and prevented retinal neurodegeneration. Our data suggest that dysregulated microglial activation (e.g., due to genetic orepigenetic alteration) can be the primary cause of retinal neuronal degeneration. Our study also suggests that active microglia may damage neurons by releasing cytotoxic cytokines such as TNFα, and CCL2. The knowledge is important for further development of strategies to control neuroinflammation and retinal degeneration.

The demand of indoor positioning solution is on the increase dramatically, and WiFi-based indoor positioning is known as a very promising approach because of the ubiquitous WiFi signals and WiFi-compatible mobile devices. Improving the positioning accuracy is the primary target of most recent works, while the excessive deployment overhead is also a challenging problem behind. In this thesis, the author is investigating the indoor positioning problem from the aspects of indoor map information and the ubiquity of WiFi signals. This thesis proposes a set of novel WiFi positioning schemes to improve the accuracy and efficiency. Firstly, considering the access point (AP) placement is the first step to deploy indoor positioning system using WiFi, an AP placement algorithm is provided to generate the placement of APs in a given indoor environment. The AP placement algorithm utilises the floor plan information from the indoor map, in which the placement of APs is optimised to benefit the fingerprinting- based positioning. Secondly, the patterns of WiFi signals are observed and deeply analysed from sibling and spatial aspects in conjunction with pathway map from indoor map to address the problem of inconsistent WiFi signal observations. The sibling and spatial signal patterns are used to improve both positioning accuracy and efficiency. Thirdly, an AP-centred architecture is proposed by moving the positioning modules from mobile handheld to APs to facilitate the applications where mobile handheld doesn’t directly participate positioning. Meanwhile, the fingerprint technique is adopted into the AP-centred architecture to maintain comparable positioning accuracy. All the proposed works in this thesis are adequately designed, implemented and evaluated in the real-world environment and show improved performance.