The role of cytosolic phospholipase A2 in microglial signaling pathways during neuroinflammation

Dissertation advisor: Dr. Grace Y. Sun.Dissertation co-advisor: Dr. Zezong Gu.Includes vita.Oxidative and nitrosative stress is known to play an important role in neurodegenerative and neuroinflammatory diseases, such as Alzheimer's disease, Parkinson's disease, ischemic[slash]hemorrhagic stroke, and traumatic brain injury. Microglia are the primary innate immune cells in the central nervous system (CNS). These cells are the first line of defense against foreign pathogens, and the exhibit multiple physiological roles including removing cellular debris and maintaining tissue homeostasis. Pathologic activation of microglia, which is frequently secondary to neurodegenerative or neuroinflammatory processes, can lead to the release of proinflammatory cytokines, reactive oxygen species (ROS), reactive nitrogenous species (RNS), excitotoxic neurotransmitters, metalloproteases, and other pro-inflammatory[slash]cytotoxic factors. Propagation of inflammation in neurodegenerative conditions and can be a contributor of neuronal cell death. Cytosolic phospholipase A2 (cPLA2) belongs to a family of phospholipases that act as the principle producers of arachidonic acid (AA) in cells. During the process of inflammation, AA released from phospholipids is metabolized by cyclooxygenase-1[slash]2 (COX1[slash]2) and lipoxygenases, and in turn can be converted to prostaglandins, prostacyclin and thromboxane. This is an important pathway of inflammation, with COX1[slash]2 being the popular target for non-steroidal anti-inflammatory drugs (NSAIDs). The role of cPLA2 and its downstream pathway has not been investigated in depth in microglial cells during CNS neuroinflammation. Using primary microglial culture prepared from cPLA2 knockout mice, we found that oxidative and nitrosative stress responses were significantly attenuated in cPLA2 knockout mice as compared with wildtype control. The same phenomenon was observed using pharmacological inhibition and siRNA knockdown of cPLA2 in BV2 microglial cells. Interestingly, unlike macrophages, inhibition of COX1[slash]2 did not result in significant decrease in oxidative[slash]nitrosative responses in BV-2 cells. Instead, lipoxygenase (LOX) inhibition, or more specifically LOX-12 and LOX-15, could significantly suppress ROS[slash]NO production in BV2 cells. Plants form the basis of traditional medicine in different civilizations throughout thousands of years. The use of herbal medicine was based on centuries of anecdotes and practitioners' experience. Recent incorporation of modern research methods to traditional medicinal investigation has shed light on the mechanism of action for many of these herbal products. Many medicinal plants and extracted compounds have been hypothesized or shown to ameliorate neurological conditions. In order to better understand the mechanism of action of botanical compounds on microglial activation pathway, an experiment was carried out in which mice were fed with control diet, elderberry diet and Sutherlandia diet for two months and followed by global cerebral ischemia by occlusion of the bilateral common carotid arteries. Mice fed with either elderberry or Sutherlandia diet demonstrated significant less motor deficits (by rotarod test). Histologic staining by cresyl violet stain showed significant decrease in neuronal cell death and decrease in microglia activation by either diet group. Immunohistochemical staining further showed colocalization of phospho-ERK and p47phox to microglial cells and decrease expression of the oxidative proteins in mice fed with either botanical diets.Includes bibliographical references

An eye tracking study of the application of gestalt theory in photography

Photography is an art form where integration of the human visual perception and psychological experiences result in aesthetic pleasure. This research utilizes eye tracking to explore the impact of the properties of Gestalt in photography on people's visual cognitive process in order to understand the psychological processes and patterns of photography appreciation. This study found that images with Gestalt qualities can significantly affect fixation, sightline distribution, and subjective evaluation of aesthetics and complexity. Closure composition images seem to make cognition simpler, resulting in the least number of fixation and saccades, longer fixation duration, and more concentrated sightline indicating stronger feeling of beauty, while images which portray similarity results in the greatest fixation and saccades, longest saccade duration, and greater scattering of sightline, indicating feelings of complexity and unsightliness. The results of this research are closely related to the theories of art and design, and have reference value for photography theory and application

Single-Image HDR Reconstruction by Learning to Reverse the Camera Pipeline

Recovering a high dynamic range (HDR) image from a single low dynamic range (LDR) input image is challenging due to missing details in under-/over-exposed regions caused by quantization and saturation of camera sensors. In contrast to existing learning-based methods, our core idea is to incorporate the domain knowledge of the LDR image formation pipeline into our model. We model the HDRto-LDR image formation pipeline as the (1) dynamic range clipping, (2) non-linear mapping from a camera response function, and (3) quantization. We then propose to learn three specialized CNNs to reverse these steps. By decomposing the problem into specific sub-tasks, we impose effective physical constraints to facilitate the training of individual sub-networks. Finally, we jointly fine-tune the entire model end-to-end to reduce error accumulation. With extensive quantitative and qualitative experiments on diverse image datasets, we demonstrate that the proposed method performs favorably against state-of-the-art single-image HDR reconstruction algorithms.Comment: CVPR 2020. Project page: https://www.cmlab.csie.ntu.edu.tw/~yulunliu/SingleHDR Code: https://github.com/alex04072000/SingleHD

Observation of Majorana fermions with spin selective Andreev reflection in the vortex of topological superconductor

Majorana fermion (MF) whose antiparticle is itself has been predicted in condensed matter systems. Signatures of the MFs have been reported as zero energy modes in various systems. More definitive evidences are highly desired to verify the existence of the MF. Very recently, theory has predicted MFs to induce spin selective Andreev reflection (SSAR), a novel magnetic property which can be used to detect the MFs. Here we report the first observation of the SSAR from MFs inside vortices in Bi2Te3/NbSe2 hetero-structure, in which topological superconductivity was previously established. By using spin-polarized scanning tunneling microscopy/spectroscopy (STM/STS), we show that the zero-bias peak of the tunneling differential conductance at the vortex center is substantially higher when the tip polarization and the external magnetic field are parallel than anti-parallel to each other. Such strong spin dependence of the tunneling is absent away from the vortex center, or in a conventional superconductor. The observed spin dependent tunneling effect is a direct evidence for the SSAR from MFs, fully consistent with theoretical analyses. Our work provides definitive evidences of MFs and will stimulate the MFs research on their novel physical properties, hence a step towards their statistics and application in quantum computing.Comment: 4 figures 15 page

Diversity of the association of serum levels and genetic variants of MHC class I polypeptide-related chain A with liver fibrosis in chronic hepatitis C

Background/Aims Genetic variants of MHC class I polypeptide-related chain A (MICA) at rs2596542 have been associated with hepatocellular carcinoma. The linkage between serum MICA (sMICA) and liver fibrosis in chronic hepatitis C is elusive. Results: Linear regression analysis revealed that sMICA were independently correlated to α-fetoprotein (β: 0.149; 95% confidence interval [CI]: 0.001, 0.003; P = 0.007)and MICA rs2596542 GG genotype (β: 0.209; 95% CI: 0.153, 0.483; P 50 pg/mL provided a positive predictive value of 72 % in predicting advanced liver fibrosis (F3-4) and of 90% in significant fibrosis (> F2) in MICA rs2596542 A allele carriers. Materials and Methods Serum level and single nucleotide polymorphism at rs2596542 of MICA were tested for the association with liver fibrosis in 319 biopsy proven chronic hepatitis C patients. Conclusions: Levels of sMICA were highly correlated to liver disease severity in chronic hepatitis C patients who carried the MICA rs738409 A allele. Patients possessing the genetic predisposition had a higher likelihood of progressed liver fibrosis if they expressed higher sMICA levels

Transmission of Bartonella henselae within Rhipicephalus sanguineus: Data on the Potential Vector Role of the Tick.

Bartonella henselae is a fastidious intraerythrocytic, gram-negative bacteria that causes cat scratch disease in humans. Ixodes ricinus has been confirmed to be a competent vector of B. henselae, and some indirect evidences from clinical cases and epidemiological studies also suggested that some other tick species, including Rhipicephalus sanguineus, may transmit the bacteria. B. henselae has been detected in R. sanguineus but no experimental investigations have been performed to evaluate the vector competency of this tick species regarding B. henselae transmission. To this end, this work aimed to assess the transstadial transmission of B. henselae between larvae and nymphs of R. sanguineus as well as transmission by nymphs infected at the larval stage. Four hundred B. henselae negative larvae were fed with B. henselae-infected blood by using an artificial membrane feeding system. After five days of feeding, B. henselae was detected by PCR in 57.1% (8/14) of engorged larval pools, 66.7% (4/6) of semi-engorged larval pools, and 66.7% (2/3) of larval feces pools. After molting, B. henselae DNA was also detected in 10% (1/10) of nymph pools, but not in tick feces. After a pre-fed step of nymphs infected at the larval stage on non-infected blood meal, B. henselae was detected by PCR in blood sample from the feeder, but no Bartonella colonies could be obtained from culture. These findings showed that B. henselae could be transstadial transmitted from R. sanguineus larvae to nymphs, and also suggest that these nymphs may retransmitted the bacteria through the saliva during their blood meal. This is the first study that validated the artificial membrane feeding system for maintaining R. sanguineus tick colony. It shows the possibility of transstadial transmission of B. henselae from R. sanguineus larvae to nymphs

Investigation of Transovarial Transmission of Bartonella henselae in Rhipicephalus sanguineus sensu lato Ticks Using Artificial Feeding

Bartonella henselae is a slow-growing, Gram-negative bacterium that causes cat scratch disease in humans. A transstadial transmission of the bacteria from larvae to nymphs of Rhipicephalus sanguineus sensu lato (s.l.) ticks, suspected to be a potential vector of the bacteria, has been previously demonstrated. The present study aims to investigate transovarial transmission of B. henselae from R. sanguineus s.l. adults to their instars. Adult ticks (25 males and 25 females) were fed through an artificial feeding system on B. henselae-infected goat blood for 14 days, and 300 larvae derived from the experimentally B. henselae-infected females were fed on noninfected goat blood for 7 days. Nested PCR and culture were used to detect and isolate B. henselae in ticks and blood samples. Bartonella henselae DNA was detected in midguts, salivary glands, and carcasses of the semi-engorged adults and pooled tick feces (during feeding and post-feeding periods). After the oviposition period, B. henselae DNA was detected in salivary glands of females (33.3%), but not in pooled eggs or larvae derived from the infected females. However, B. henselae DNA was detected by nested PCR from the blood sample during larval feeding, while no viable B. henselae was isolated by culture. According to our findings, following infected blood meal, B. henselae could remain in the tick midguts, move to other tissues including salivary glands, and then be shed through tick feces with limited persistency. The presence of bacterial DNA in the blood during larval feeding shows the possibility of transovarial transmission of B. henselae in R. sanguineus s.l. ticks