3,844 research outputs found

    A Spark Of Emotion: The Impact of Electrical Facial Muscle Activation on Emotional State and Affective Processing

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    Facial feedback, which involves the brain receiving information about the activation of facial muscles, has the potential to influence our emotional states and judgments. The extent to which this applies is still a matter of debate, particularly considering a failed replication of a seminal study. One factor contributing to the lack of replication in facial feedback effects may be the imprecise manipulation of facial muscle activity in terms of both degree and timing. To overcome these limitations, this thesis proposes a non-invasive method for inducing precise facial muscle contractions, called facial neuromuscular electrical stimulation (fNMES). I begin by presenting a systematic literature review that lays the groundwork for standardising the use of fNMES in psychological research, by evaluating its application in existing studies. This review highlights two issues, the lack of use of fNMES in psychology research and the lack of parameter reporting. I provide practical recommendations for researchers interested in implementing fNMES. Subsequently, I conducted an online experiment to investigate participants' willingness to participate in fNMES research. This experiment revealed that concerns over potential burns and involuntary muscle movements are significant deterrents to participation. Understanding these anxieties is critical for participant management and expectation setting. Subsequently, two laboratory studies are presented that investigated the facial FFH using fNMES. The first study showed that feelings of happiness and sadness, and changes in peripheral physiology, can be induced by stimulating corresponding facial muscles with 5–seconds of fNMES. The second experiment showed that fNMES-induced smiling alters the perception of ambiguous facial emotions, creating a bias towards happiness, and alters neural correlates of face processing, as measured with event-related potentials (ERPs). In summary, the thesis presents promising results for testing the facial feedback hypothesis with fNMES and provides practical guidelines and recommendations for researchers interested in using fNMES for psychological research

    Surface-Enhanced Coherent Raman scattering (SE-CRS) with Noble Metal Nanoparticles

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    Early cancer detection remains challenging due to numerous complex tempo-spatial metabolic changes in cell physiology. Based on their ability to recognise molecular structures and pathological changes at molecular levels, spectroscopic have recently emerged as promising non-invasive, non-ionising, and cost-efficient tools to help detect cancer, and other human pathologies. Raman spectroscopy is a valuable technique that provides information regarding the chemical properties of materials. Nevertheless, it has limitations due to the limited amount of Raman light scattered. Strategies for cancer diagnostics and therapies are based on the hypothesis that nanoparticles (NPs) can be precisely tailored to target cancer cells. However, the tools required to image NPs at cellular levels remain scarce in the literature. The work outlined in this thesis, for the first time, utilises noble metal NPs and Raman reporters, with the mechanisms of surface enhanced Raman scattering (SERS) and coherent anti-Stokes Raman scattering (CARS), in cancer cells and tumour spheroids to address the demerits of low spatial resolution, signal-to-noise ratio, and chemical specificity. SERS and CARS have broadly been explored in this regard. To increase the effectiveness of Raman scattering, a variety of techniques have been devised to boost its intensity. Primarily, I studied four techniques to increase Raman scattering intensity with the ultimate objective of improving sensitivity and assessing limits of various Raman methods: SERS, surface-enhanced coherent anti-Stokes Raman scattering (SE-CARS), surface-enhanced stimulated Raman scattering (SE-SRS), and broadband coherent anti-Stokes Raman scattering (BCARS). Coherent Raman scattering (CRS) is utilised to enhance weak Raman bands. The signal is enhanced by nonlinear interaction of the excitation lasers within the sample. Despite the advantages offered over Raman, CRS has been relatively unexploited for image Raman tagged NPs. This challenge has recently been addressed using surface plasmon enhancement, which gives significantly enhanced inelastic scattering signals as well as reduced signal-to-noise ratio. Surface-enhanced coherent Raman scattering (SE-CRS) has been characterised by using a variety of techniques such as SERS, CARS, and SE-CARS. This work provides a step forward to develop plasmon enhanced SRS and CARS in addressing critical biological questions using nonlinear bio-photonics. In the first part of this thesis, I developed a reproducible substrate that mimics gold nanoparticles (AuNPs) and allows forward detection which is critical for CRS. I investigated the effects of annealing on gold films deposited on glass substrates with thicknesses from 3 nm to 15 nm as described in depth in chapter 5. In addition to this, it provides an explanation of the work that was performed to explore the interaction between Raman tags BPT (biphenyl-4-thiol), BPE trans-1,2-bis(4-pyridyl) ethylene, and IR 820 (new indocyanine green) on gold films substrates using 785 nm laser excitation. In the second part of this thesis, I investigated the interactions between Raman tags of BPT on gold films substrates using CRS and broadband CARS techniques. These experiments also offer the SE-CRS enhancement signal. The research done to examine gold thin film substrates and to offer SE-SRS and SE-CARS enhancement signals in the fingerprint region as described in chapter 6. Using CRS microscopy, the investigations in this chapter study these interactions. In the third part of this thesis, I developed a novel imaging methodology for the visualisation of AuNPs inside cellular structures and spheroids, with the intention of acquiring distinct spectroscopic fingerprints. Consequently, I undertook the task of devising protocols for visualising AuNPs and Raman reporter molecules within cancer cell models, spheroids, and animal tissues as described in chapter 7. The aim was to attain distinctive spectroscopic profiles by employing the SE-CRS technique, achieved by illuminating AuNPs along with Raman reporter molecules (BPT, BPE, IR 820) using low intensity infrared light, with both the pump and Stokes beams operating at intensities below 0.2 mW. In summary, this thesis sheds light on the development of surface plasmon resonance phenomena based on metallic nanostructures for use in nonlinear inelastic scattering systems, including surface-enhanced Raman scattering (SERS), coherent Raman scattering (CRS), and surface-enhanced coherent Raman scattering (SE- CRS). The primary focus is to use this system for disease diagnostics, rooted in SERS, reflects a commitment to advancing cancer diagnostics, based on SERS thereby enhancing the precision and discrimination of molecular signals, making a significant stride towards more effective and nuanced cancer diagnostics

    Defining novel regulators of inflammatory signalling in pancreatic cancer

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    Pancreatic ductal adenocarcinoma (PDAC) remains a cancer with few effective therapeutic options and, for patients with this disease, the prognosis remains extremely poor. In recent years immunotherapy has emerged as a promising treatment modality for a number of different tumour types but so far its impact in treatment of PDAC has been limited. Examining the molecular pathways that determine the immune response to cancer cells in PDAC will enable development of new therapeutic strategies to target this response. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ T cell infiltration. The Serrels Laboratory has already demonstrated a role for FAK in promoting tumour evasion by inducing an immunosuppressive microenvironment, specifically by regulation of cytokines. This has led to trials of the FAK inhibitor (defactinib) in conjunction with immunotherapy. I proposed that FAK was likely to regulate further chemokine/cytokine and ligand receptor networks and that by understanding more about these networks it may be possible to target potential pathways to modify this response and provide therapeutic benefit. I used CRISPR, Forward Phase Protein Arrays (FPPA) and ELISA on mouse and human PDAC cell lines to examine relative expression of chemokines and cytokines and how this expression was regulated by FAK. I identified CXCL16 as one of the most abundantly expressed cytokines in both mouse and human cell lines and one of the most significantly increased cytokines upon FAK depletion. PDAC FAK null cell lines +/- CXCL16 were then orthotopically implanted into the pancreas of C57BL/6 mice and I demonstrated that CXCL16 depletion resulted in a re-programming of the immune cell tumour infiltrate with reduced tumour growth. These findings identify a FAK dependent CXCL16-CXCR6 paracrine signalling axis that may represent a mechanism of resistance to FAK inhibition and thus an important potential therapeutic target

    Hydrogen-bonding receptors for anion recovery in a capacitive deionisation system

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    Receptors are ubiquitous throughout nature and are found heavily within biological systems. This has led to synthetic supramolecular chemists to modify or develop analogous mimics of these receptors with high affinity and specificity for a range of target compounds, for potential commercial use. One group of particular interest are receptors that function through the formation of hydrogen bonds to the guest species. This class of receptor has been shown to have a range of different structural geometries and binding motifs, that allow for the sequestration of a number of different species. In the context of this work, anionic hydrogen-bonding receptors, specifically for ‘phosphate’- in most cases dihydrogenphosphate- and bicarbonate are of interest. Phosphate is an integral part of the DNA backbone, however a organophosphorus containing compounds also comprise a large group of chemical weapons which can have a devasting impact on the bodies ability to function. Chemical weapon compounds, such as sarin and Novichok, are based on the functionalisation of a central phosphate core which can be biotransformed into a highly potent active species within the body. Phosphate is also an essential component of plant fertilizers and is used on a huge scale in order to maintain global food security. However, phosphate loss as a consequence of agricultural run-off leads to reduced availability of essential minerals as well as large scale eutrophication. One such method that could be utilised for the recovery of phosphate is electrochemical capacitive deionisation. The principle and idea of capacitive deionisation has been around since the late 1960’s to early 1970’s and has been shown to be a suitable method for the desalination of low-to-medium salinity input streams. The purpose of the work within this thesis was to modify and synthesise receptors that could be covalently attached to porous carbon electrodes and impart selectivity to a capacitive deionisation system. In Chapter 1, the importance of ‘phosphate’, biologically and commercially is addressed before an in depth look at some of the phosphate specific hydrogen bonding receptors that have been reported in the literature. The design of a successful hydrogen bonding receptor relies on the correct orientation of the binding motifs and the range of structural scaffolds have been shown to be useable. Following this, the electrochemical principles of capacitive deionisation and its suitability for the recovery of phosphate are detailed, including some examples of capacitive deionisation set-ups and the overall processes involved. Chapter 2 details the theory of the techniques used throughout this thesis, which include, but not limited to, 1H and 13C NMR for the structural elucidation of the synthesised receptors and cyclic voltammetry which was used for the attachment of organic groups to an electrode. The historical and theoretical background established in Chapters 1 and 2 will lead into the work undertaken in Chapters 3-5. Chapter 3 focusses on the first of three hydrogen bonding receptors synthesised. Building upon previous work within the field, two neutral indole-based receptors were modified to include two different potential attachment points for the electrode- a carboxylic acid and an alkyne. Following the successful synthesis of the alkyne-based receptor, 1H NMR titrations were used to confirm the affinity of the new receptor for dihydrogenphosphate. Chapter 4 introduces the second anion of interest, bicarbonate. The underlying principles for hydrogen bonding are the same for bicarbonate, as in phosphate, however a different receptor was synthesised. The carbazole receptor synthesised contained free amine groups that were proposed to act as points of attachment to an already surface bound organic spacer group. 1H NMR titrations are once again used to determine the affinity of the receptor for the bicarbonate anion. Finally, Chapter 5 introduces the second of the dihydrogenphosphate-specific receptors, this time based on the amino acid leucine. UVVis titrations with a number of different anions were used to determine the affinity of the receptor. Within this chapter, methods for the attachment of organic groups are detailed including the electroreduction of 4-nitrobenzene diazonium and the direct oxidation of the alkyne

    Explainable Semantic Medical Image Segmentation with Style

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    Semantic medical image segmentation using deep learning has recently achieved high accuracy, making it appealing to clinical problems such as radiation therapy. However, the lack of high-quality semantically labelled data remains a challenge leading to model brittleness to small shifts to input data. Most works require extra data for semi-supervised learning and lack the interpretability of the boundaries of the training data distribution during training, which is essential for model deployment in clinical practice. We propose a fully supervised generative framework that can achieve generalisable segmentation with only limited labelled data by simultaneously constructing an explorable manifold during training. The proposed approach creates medical image style paired with a segmentation task driven discriminator incorporating end-to-end adversarial training. The discriminator is generalised to small domain shifts as much as permissible by the training data, and the generator automatically diversifies the training samples using a manifold of input features learnt during segmentation. All the while, the discriminator guides the manifold learning by supervising the semantic content and fine-grained features separately during the image diversification. After training, visualisation of the learnt manifold from the generator is available to interpret the model limits. Experiments on a fully semantic, publicly available pelvis dataset demonstrated that our method is more generalisable to shifts than other state-of-the-art methods while being more explainable using an explorable manifold

    Dissecting Extracellular Matrix Internalisation Mechanisms using Functional Genomics

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    Breast and ovarian malignancies account for one third of female cancers. The role of the stroma in supporting invasive growth in breast cancer has become clear. Breast cancer cells interact and respond to the cues from the surrounding extracellular matrix (ECM). Integrins are main cell adhesion receptors and key players in invasive migration by linking the ECM to the actin cytoskeleton. In addition, integrins mediate distinctive biochemical and biomechanical signals to support cancer invasion. The role of matrix proteases in promoting ECM degradation and cancer dissemination has been extensively studied; however, cancer cells possess additional means to support those processes, such as integrin-mediated ECM endocytosis and consequent degradation in the lysosomes. Internalisation of the extracellular matrix is upregulated in invasive breast cancer. Nonetheless, the mechanisms by which cancer cells regulate this process are poorly understood. We developed a high throughput pH sensitive system to detect ECM uptake. Here, we show that MDA-MB-231 breast cancer cells converge in macropinocytosis to internalise diverse ECM components and we confirm that this process is modulated by PAK1. To unravel which ECM components breast cancer cells internalise in a complex environment (namely, cell derived matrices), we performed mass spectrometry. Proteomic analysis identified Annexin A6, Collagen VI, Tenascin C and fibronectin, among other matrisome proteins, to be internalised by invasive breast cancer cells. Following ECM endocytosis, ECM is targeted for lysosomal degradation. To unravel the molecular mechanisms behind this process, we performed a trafficking screen and identified the AP3 complex, VAMP7, Arf1 and ARFGEF2. Our results suggest that the AP3 complex may regulate ECM-integrin delivery to lysosomes. To gain more insight on the signalling pathways governing macropinocytosis in breast cancer cells, we performed a kinase and phosphatase screen that unravelled MAP3K1 and PPP2R1A, a subunit of protein phosphatase 2A (PP2A) as relevant regulators of ECM endocytosis. Furthermore, our data suggests that p38 mitogen-activated protein kinase (MAPK) activation upon binding to the ECM is required for ECM macropinocytosis. Outstandingly, inhibiting p38 MAPK led to profound changes in the ability of breast cancer cells to migrate in cell derived matrices. Previous work from the Rainero lab focused on characterising the receptors involved in ECM internalisation; α2β1 integrin was identified as the main regulator of ECM uptake in MDA-MB-231 cells. In particular, α2β1 integrin has been shown to activate p38 MAPK pathway. Taken together, we hypothesise that binding of ECM to α2β1 integrin results in the activation of PAK1 and MAP3K1, which in turn leads to ECM endocytosis. p38 MAPK activity may induce changes in actin polymerisation via PPP2R1A and/or focal adhesion turnover, which consequently promotes ECM macropinocytosis and invasive migration

    Introduction to Psychology

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    Introduction to Psychology is a modified version of Psychology 2e - OpenStax
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