Fearing the wurst : Robust approach bias towards non-vegetarian food images in a sample of young female vegetarian eaters

Peer reviewedPostprin

Targeting the M1 muscarinic acetylcholine receptor in neurodegeneration

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and to date, no disease-modifying treatments exist. The M1 muscarinic acetylcholine receptor (mAChR) is an established therapeutic target for the symptomatic treatment of AD, and drugs activating the M1 mAChR have been shown to improve cognitive decline and behavioural symptoms in several clinical trials. Pre-clinical evidence also suggests that M1 mAChRs may also have disease-modifying effects in neurodegeneration, such as modification of the classical AD hallmarks, amyloid β (Aβ) and tau. Due to the conserved nature of the classic orthosteric binding site of the five mAChR subtypes, targeting one subtype via this binding site specifically has proved challenging. The development of compounds targeting the less conserved allosteric site has enabled significant improvements in subtype selectivity. Chronic dosing with the M1 mAChR positive allosteric modulator (PAM) VU0486846 has demonstrated disease-modifying potential in a murine prion model of terminal neurodegeneration and in an Aβ-based genetic AD model. This thesis aimed to assess the effect of chronic treatment with the M1 mAChR PAM VU0486846 in the rTG4510 tauopathy mouse model. The results show that VU0486846 did not affect the expression of neuropathological markers of disease, such as phosphorylated tau and glial fibrillary acidic protein, but reversed elevated levels of coagulation factor III and cystatin C that were observed in diseased mice when compared to controls. The normalisation of coagulation factor III and cystatin C, which have both been shown to be dysregulated in AD patients, remains an interesting avenue for further research. As part of trying to understand the potential of the M1 mAChR as a drug target, it is crucial to also determine receptor localisation. Therefore, this thesis also aimed to assess M1 mAChR distribution in the brain using a M1-monomeric enhanced green fluorescent protein (meGFP) mouse line, which expresses the meGFP tagged version of the M1 mAChR in the endogenous gene locus. Tissue clearing was used to visualise the receptor and a range of studies was performed to explore the utility of the meGFP-tagged M1 mAChR. Overall, this thesis identified some novel changes following chronic treatment with a M1 mAChR PAM in a tauopathy mouse model, which warrant further investigation to fully evaluate the potential of targeting the M1 mAChR in neurodegeneration

“This Story Is Right On”: The Impact of Regulatory Fit on Narrative Engagement and Persuasion

When people read a story, feelings of rightness from regulatory fit (consistency between regulatory state and strategic means) could suggest that the story is “right on” relative to feelings of wrongness from regulatory nonfit. Under these conditions, individuals who are experiencing feelings of rightness should engage more with the narrative and be more persuaded by its implicit messages. Results from two experiments supported these hypotheses. Participants in Experiment 1 were more mentally engaged (transported) by the story when they experienced regulatory fit. We replicated this effect in Experiment 2 and extended it to endorsement of story-consistent beliefs, an indicator of persuasion via narratives. Additionally, we found that drawing participants\u27 attention to an earlier event as a source of feelings of rightness eliminated the regulatory fit effects on transportation and persuasion, suggesting attribution of feelings of regulatory fit/nonfit to the plausibility of the narrative world

Heterosexist Harassment and Rejection, Emotional Social Support and Perceived Stress in a Lesbian, Gay and Bisexual Sample

The minority stress theory suggests LGBs experience greater stress levels due to their sexual minority identities; thus, they are more prone to psychological distress. Poor mental health is linked to internalized homophobia and heterosexism. However, affirmative social support may mitigate the stress response via the buffering hypothesis. My model posits that LGBs are more likely to report perceived stress; however, affirmative social support can mitigate stress. I investigated the relationship between perceived stress and sexual minority identity. I explored the relationship between heterosexism, emotional support and perceived stress and the moderating role of social support in my LGB sample. I conducted a hierarchical linear regression to test my model, which accounted for 29% of the variance in perceived stress. Heterosexism and emotional support were significantly associated with perceived stress. I failed to find a moderating role of emotional support. Limitations, strengths, future research and implications are discussed

A copper-catalyzed asymmetric oxime propargylation enables the synthesis of the gliovirin tetrahydro-1,2-oxazine core

The bicyclic tetrahydro-1,2-oxazine subunit of gliovirin is synthesized through a diastereoselective copper-catalyzed cyclization of an N-hydroxyamino ester. Oxidative elaboration to the fully functionalized bicycle was achieved through a series of mild transformations. Central to this approach was the development of the first catalytic, enantioselective propargylation of an oxime to furnish a key N-hydroyxamino ester intermediate

CT-Based Attenuation Correction in I-123-Ioflupane SPECT

Purpose Attenuation correction (AC) based on low-dose computed tomography (CT) could be more accurate in brain single-photon emission computed tomography (SPECT) than the widely used Chang method, and, therefore, has the potential to improve both semi-quantitative analysis and visual image interpretation. The present study evaluated CT-based AC for dopamine transporter SPECT with I-123-ioflupane. Materials and methods Sixty-two consecutive patients in whom I-123-ioflupane SPECT including low-dose CT had been performed were recruited retrospectively at 3 centres. For each patient, 3 different SPECT images were reconstructed: without AC, with Chang AC and with CT-based AC. Distribution volume ratio (DVR) images were obtained by scaling voxel intensities using the whole brain without striata as reference. For assessing the impact of AC on semi-quantitative analysis, specific-to-background ratios (SBR) in caudate and putamen were obtained by fully automated SPM8-based region of interest (ROI) analysis and tested for their diagnostic power using receiver-operator- characteristic (ROC) analysis. For assessing the impact of AC on visual image reading, screenshots of stereotactically normalized DVR images presented in randomized order were interpreted independently by two raters at each centre. Results CT-based AC resulted in intermediate SBRs about half way between no AC and Chang. Maximum area under the ROC curve was achieved by the putamen SBR, with negligible impact of AC (0.924, 0.935 and 0.938 for no, CT-based and Chang AC). Diagnostic accuracy of visual interpretation also did not depend on AC. Conclusions The impact of CT-based versus Chang AC on the interpretation of I-123-ioflupane SPECT is negligible. Therefore, CT-based AC cannot be recommended for routine use in clinical patient care, not least because of the additional radiation exposure

Tables or Bar Graphs? Presenting Test Results in Electronic Medical Records

Electronic personal health records offer a promising way to communicate medical test results to patients. We compared the usability of tables and horizontal bar graphs for presenting medical test results electronically

Experimental infection of conventional nursing pigs and their dams with \u3ci\u3ePorcine deltacoronavirus\u3c/i\u3e

Porcine deltacoronavirus (PDCoV) is a newly identified virus that has been detected in swine herds of North America associated with enteric disease. The aim of this study was to demonstrate the pathogenicity, course of infection, virus kinetics, and aerosol transmission of PDCoV using 87 conventional piglets and their 9 dams, including aerosol and contact controls to emulate field conditions. Piglets 2–4 days of age and their dams were administered an oronasal PDCoV inoculum with a quantitative real-time reverse transcription (qRT)-PCR quantification cycle (Cq) value of 22 that was generated from a field sample having 100% nucleotide identity to USA/Illinois121/2014 determined by metagenomic sequencing and testing negative for other enteric disease agents using standard assays. Serial samples of blood, serum, oral fluids, nasal and fecal swabs, and tissues from sequential autopsy, conducted daily on days 1–8 and regular intervals thereafter, were collected throughout the 42-day study for qRT-PCR, histopathology, and immunohistochemistry. Diarrhea developed in all inoculated and contact control pigs, including dams, by 2 days post-inoculation (dpi) and in aerosol control pigs and dams by 3–4 dpi, with resolution occurring by 12 dpi. Mild to severe atrophic enteritis with PDCoV antigen staining was observed in the small intestine of affected piglets from 2 to 8 dpi. Mesenteric lymph node and small intestine were the primary sites of antigen detection by immunohistochemistry, and virus RNA was detected in these tissues to the end of the study. Virus RNA was detectable in piglet fecal swabs to 21 dpi, and dams to 14–35 dpi

Gene signatures from scRNA-seq accurately quantify mast cells in biopsies in asthma

Respiratory disease, characterized by changes in the cells of the lung, can affect molecular phenotype of cells and the intercellular interactions, resulting in a disbalance in the relative proportions of individual cell types. Understanding these changes is essential to understand the pathophysiology of lung disease. Conventional 'bulk' RNA-sequencing (RNA-seq), analyzing the entire transcriptome of the tissue sample, provides information about average expression levels of each gene in the mixed cell population; whereas it does not consider the cellular heterogeneity in samples composed of more than one cell type 1 . Single-cell RNA-seq (scRNA-seq) assesses the transcriptome of a complex biological sample with single-cell resolution, allowing identification of the relative frequency of discrete cell-types and analysis of their transcriptomes 1 . Nevertheless, analyzing the transcriptomic signature in large numbers of patients by scRNA-Seq is currently limited by its high costs. Mast cells are key regulatory cells driving the inflammatory process in asthma2 . Since they can be quantified by immunohistochemical staining for validation purposes, we used mast cells as an example of a rare cell population to assess the validity of our deconvolution approach. Recently, a number of bulk RNA-seq deconvolution methods have become available 3 , for instance of two deconvolution methods, namely support vector regression (SVR) 4 , the machine-learning method implemented in CYBERSORT, and Non-Negative Least Square (NNLS) 5 , using a matrix of cell-type selective genes identified with AutoGeneSc 6 . Both approaches are designed to estimate relative proportion of the main, common cell types present in the sample. When we used these methods to estimate the number of mast cells, we found a poor correlation with the number of mast cells stained by immunohistochemistry in the biopsies, suggesting the CIBERSORT and NNLS are less reliable in the case of rare cell types. We explored the possibility to use scRNA-Seq data from small numbers of subjects to specifically interrogate the relative cell type frequency of a rare cell population in a bulk RNA-Seq dataset obtained from a large asthma cohort