1,564 research outputs found

    The role of the oral microbiome in the immunobullous diseases pemphigus vulgaris and mucous membrane pemphigoid and oral lichen planus

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    Saliva is formed from contributions of salivary glands and the serum exudates principally from gingival margins or damaged mucosa combined with components derived from the environment, including a community of microorganisms - the microbiome. I postulate that changes in microbial diversity and population structure play key roles in the modulation of host- microbial interactions which influence both the hypersensitive autoimmune responses and inflammation seen in these inflammatory mucocutaneous disorders. For my research, a total of 186 participants were recruited: 48 mucous membrane pemphigoid (MMP), 48 pemphigus vulgaris (PV), 50 oral lichen planus (OLP) patients, and 40 healthy controls. Unstimulated whole saliva, subgingival plaque, serum, and plasma samples were collected from 186 participants. In addition, metadata were collected on the following covariates: age, gender, ethnicity, type of the diet, disease history and therapeutic intervention in the preceding six months. Oral disease severity scores (ODSS) were assessed, and periodontal status was examined using a periodontal six pocket chart. To characterise microbiome profiles, saliva and subgingival plaque were processed for sequencing genomic DNA using the NGS Shotgun metagenomics sequencing technique. Inflammatory cytokines and proteases were investigated in saliva and serum using Human Magnetic Luminex Screening Assay (R&D Systems). Selected cytokines were analysed by enzyme-linked immunosorbent assay (ELISA) technique (R&D Systems) to determine host inflammatory responses in saliva and serum samples. Additionally, saliva and plasma samples were analysed for metabolites by nuclear magnetic resonance (NMR). Significant increases in periodontal score (PISA) in all three groups of disease were identified compared to healthy control group with significant positive correlation between oral disease severity (ODSS) and PISA in OLP and PV groups. All three groups of diseases had significantly higher levels of inflammatory Th2/Th17 cytokines (IL-6, IL-13 and IL-17 in saliva samples), as well as higher levels of MMP-3 matrixins in saliva. In addition, there were positive correlations between ODSS and salivary IL-6, IL-13 and MMP-3 in saliva of OLP, salivary and serum levels of IL-6 and MMP-3 in MMP group, and significant association of salivary IL-6, IL-1β and MMP-3 in PV group. Metabolomic data showed that saliva is a better biofluid for correlation of the metabolomic profile with oral disease severity than plasma. Salivary ethanol was corelated with disease severity in the OLP group, whereas in PV was a strong correlation of ODSS with choline. Finally, a unique microbial community was found in each group of diseases. In the MMP group, ODSS was significantly correlated with L. hofstadii, C. sputigena, N. meningitidis, N. cinerea and P. sacchar0lytica. In PV, a positive correlation was found with F. nucleatum, G. morbillorum, and E. corrodens, G. elegans, H. sapiens and T. vincentii. In OLP, the disease tends to worsen when there was reduced abundance of X. cellulosilytica, Actinomyces ICM 47, S. parasanguinis, S. salivarius, L. mirabilis and O. sinus. Lower microbial diversity was correlated with ODSS in saliva and plaque of the OLP group. In conclusion, this study provides strong evidence of the complex interplay between the oral microbiome, immunological factors, and metabolites in the context of immunobullous diseases and OLP. The findings highlight the integral role of oral bacteria in disease progression, the significance of immune dysregulation, and the potential impact of specific microbial species and metabolic pathways. These insights give the way for further research and clinical applications, offering the promise of personalized approaches for diagnosis, and management of OLP, MMP and PV. Future investigations should focus on discovering the mechanistic details underlying these associations and validating the identified biomarkers in larger patient cohorts, ultimately contributing to a deeper understanding of the pathogenesis of these conditions

    Achieving social justice for psychiatric survivors: capabilities and advance consent to mental health treatment

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    This thesis uses a socio-legal methodology to investigate the desirability of advance consent to mental health treatment. Advance consent to mental health treatment is an anticipatory directive whereby a mentally ill patient may self-bind to future treatment in specific circumstances. Currently, there is no such provision available in English law. To assess the desirability of advance consent, this thesis asks the following questions: 1) To what extent would advance consent to mental health treatment be able to minimise coercion in the experiences of treatment? 2) What role, if any, should the mental capacity assessment play in facilitating a legal framework for advance consent? 3) Which capabilities are valued by psychiatric survivors, and to what extent can advance consent translate into securing those? 4) What are the sources of injustice experienced by psychiatric survivors, and what challenges/barriers do they pose for advance consent? These questions are grounded in original empirical data based on 21 interviews with 12 psychiatric survivors using narrative and photo- elicitation methods. These methods are considered novel for the socio-legal inquiry into mental health law. Thus, this thesis suggests a new methodological approach for studying lived experience of mental health law in everyday life. This socio-legal analysis is driven by the capabilities approach developed primarily by Martha Nussbaum and Amartya Sen. I argue that social justice is best understood through capabilities and practical alternatives to what is currently experienced as injustice in people’s lives. I suggest advance consent can aid the individual experience or achievement of social justice by supporting capabilities necessary for bodily integrity, health, emotions and safety, making it a desirable mechanism. This is the first study to use the capabilities approach to conceptualise lived experiences of mental health and treatment to provide a new contribution to existing debates on advance consent. In my investigation, I find that coercion, insufficient information, insight, stigma and mental capacity are experienced as injustice. I argue that legally binding, voluntary, informed, sufficiently safeguarded, and carefully implemented advance consent can minimise these experiences of injustice. Using empirical data alongside the capabilities framework enables a more holistic and practical consideration of the value of advance consent in everyday life and in relation to social justice

    The role of AD protective variant PLCγ2P522R in modulating microglia mediated clearance and synaptic pruning

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    PLCG2-P522R, a rare coding variant in the Phospholipase C gamma-2 (PLCG2) gene, has been found to be protective against late onset Alzheimer's disease (AD). Within the central nervous system, PLCγ2 is most abundantly expressed in microglia, and microglial mediated neuroinflammatory system has emerged as a major contributor to the molecular and phenotypic changes observed in the AD brain. However, the mechanism by which the P522R variant of PLCγ2 reduces AD pathology is still unknown. BV2 (mouse microglia) cells and human induced pluripotent stem-cells (hiPSC) derived microglia were used in this thesis work to evaluate the role of PLCγ2 in modifying various disease-relevant microglia functions. PLCγ2WT and PLCγ2P522R expression constructs were transfected into BV2 cells to examine the effects of PLCγ2 overexpression on various microglia functions including amyloid beta (Aβ) clearance and synaptic targeting, and various transcriptional changes linked to AD. hiPSCs were genome edited using CRISPR/Cas9 to generate both heterozygous and homozygous forms of the PLCG2_P522R variant in healthy controls. These hiPSC derived microglia were used to explore the effects of the PLCγ2P522R basal level on disease-relevant processes, such as microglial capacity to uptake Aβ and synapses. Microglia transcriptional changes were examined using targeted qPCR analysis to investigate changes in expression of key microglial genes. Mitochondrial function and calcium level changes were also investigated in these microglia cells to determine their metabolic fitness. In addition, the microglia were subjected to acute and chronic treatment of oligomeric Aβ to examine the impact of PLCγ2P522R on microglia's ability to respond to acute and chronic stress. As a result, the effects of Aβ oligomers on lysosomal biogenesis and phagocytic capacities of these microglia were examined further. As a result of PLCγ2 overexpression, Aβ uptake and other immune- provoking cargoes like zymosan were significantly increased. In contrast, the uptake of synaptosomes in BV2 cells overexpressing PLCγ2 was considerably reduced. Similarly, microglia generated from hiPSCs also showed enhanced clearance of Aβ and preservation of synapses by PLCγ2P522R variants. In the PLCγ2P522R microglia variants, the expression of multiple genes, including IL-10 and CX3CR1, as well as mitochondrial function, cytoplasmic calcium flux, and cellular motility were all increased. It was found that the protective effect of PLCγ2P522R was vitally dependent on 'allelic-dose', as homozygous cells displayed a lower preservation of synapse and a distinct gene expression profile compared to heterozygous cells. Similarly, microglia with the protective mutation PLCγ2P522R displayed higher inflammatory cytokine IL-1β level, and better response to acute treatment with Aβ oligomers. PLCγ2P522R appeared to resist the quiescence that was seen in WT microglia variants, by increasing cytokine production and lysosomal biogenesis. My findings suggest that the P522R variant in PLCγ2 increases microglia capacity to clear toxic aggregates such as Aβ while preserving synapses. Furthermore, my findings suggests that PLCγ2P522R contributes to greater microglial surveillance, as well as microglia priming towards a pro-inflammatory state, along with an increased capacity to adapt to growing energy demands. This, however, also shows the delicate balance of this system, as increasing the 'dosage' of PLCγ2P522R may result in diminished favourable benefits

    2017 GREAT Day Program

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    SUNY Geneseo’s Eleventh Annual GREAT Day.https://knightscholar.geneseo.edu/program-2007/1011/thumbnail.jp

    Morphometric reorganization induced by working memory training: perspective from vertex and network levels

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    Der sich beschleunigende globale Alterungsprozess und die Tatsache, dass sich die kog-nitiven Fähigkeiten mit dem Alter verschlechtern, was sich erheblich auf die Lebensquali-tät älterer Erwachsener auswirkt, insbesondere bei altersbedingten Störungen (z. B. kogni-tiver Beeinträchtigung, Demenz), weisen auf einen dringenden Bedarf an Ansätzen zum Schutz und zur Verbesserung der kognitiven Fähigkeiten sowie an Untersuchungen der neuronalen Substrate altersbedingter Veränderungen und der Neuroplastizität hin. Da man davon ausgeht, dass das Arbeitsgedächtnis (WM) die grundlegende Ursache für altersbe-dingte kognitive Beeinträchtigungen bei einer Vielzahl von kognitiven Fähigkeiten dar-stellt, ist das Arbeitsgedächtnistraining (WMT) zu einem aktuellen Thema und einem be-liebten Ansatz geworden. Frühere Studien haben gezeigt, dass das Arbeitsgedächtnistrai-ning (WMT) die kognitive Leistung verbessert. Die spezifischen Auswirkungen sowie die zugrunde liegenden neurobiologischen Mechanismen sind jedoch nach wie vor um-stritten. Ziel dieser Arbeit ist es, die durch das WMT induzierte neuronale strukturelle Plastizität auf mehreren Ebenen sowie die Verhaltenseffekte des WMT zu untersuchen. In der ers-ten Studie untersuchten wir die topographischen Veränderungen der Morphologie der grauen Substanz durch WMT, indem wir vier strukturelle Metriken (d.h. die kortikale Dicke, das kortikale Volumen, die kortikale Oberfläche und den lokalen Gyrifikationsin-dex, LGI) sowie die subkortikalen Volumina explorierten. Konkret wurden 59 gesunde Probanden mittleren Alters nach dem Zufallsprinzip entweder einem adaptiven WMT oder einer nicht-adaptiven Intervention zugewiesen. Alle Teilnehmer unterzogen sich vor und nach der 8-wöchigen WMT-Phase einer Neurobildgebung sowie kognitiven Tests. Vor und nach dem WMT wurden vier kortikale Metriken auf Scheitelpunktniveau und sieben subkortikale Volumina sowie die globale mittlere kortikale Dicke berechnet. Das wich-tigste Ergebnis war, dass die WMT-Gruppe im Vergleich zur aktiven Kontrollgruppe eine größere Zunahme der kortikalen Faltung in den bilateralen parietalen Regionen zeigte. Die Ergebnisse deuten darauf hin, dass strukturelle Veränderungen durch WMT in WM-bezogenen Regionen, insbesondere in parietalen Regionen, die Verarbeitung einer höhe-ren WM-Belastung erleichtern können. Darüber hinaus könnte die kortikale Faltung das relevanteste und plastischste Merkmal von WM und Lernen sein und WMT-Effekte stär-ker widerspiegeln als andere Metriken. Basierend auf den Ergebnissen der ersten Studie haben wir darüber hinaus untersucht, ob die trainingsinduzierten Effekte des WMT in der kortikalen Faltung auf Vertex-Ebene von topologischen Veränderungen begleitet werden. Zu diesem Zweck untersuchten wir in Studie zwei die durch WMT verursachte Plastizität auf Netzwerkebene mit Hilfe eines strukturellen Kovarianzansatzes (SC), der auf denselben Stichproben basiert. Es wurden gyrifikationsbasierte SC-Matrizen für jede Gruppe vor und nach dem Training sowie lon-gitudinale gyrifikationsbasierte SC-Matrizen erstellt. Innerhalb jeder Gruppe ergab die LGI-basierte SC-Analyse keine Hinweise auf WMT-induzierte Veränderungen der kor-tiko-kortikalen Verbindungen, weder in der WMT- noch in der aktiven Kontrollgruppe. Die Ergebnisse der longitudinalen SC-Analyse (unkorrigiert p < 0,005) zeigten, dass die trainingsinduzierten Veränderungen der kortikalen Faltungsintensität signifikante Unter-schiede zwischen Paaren von parietalen Regionen sowie Paaren von frontalen Regionen aufwiesen. Insgesamt deuten die kombinierten Ergebnisse dieser beiden Studien darauf hin, dass ers-tens WMT neuronale strukturelle Plastizität hervorrufen kann; zweitens die kortikale Fal-tung das relevanteste und plastischste Merkmal von WM und Lernen sein könnte, das die Auswirkungen von WMT besser widerspiegelt als andere Indikatoren auf Vertex-Ebene; und drittens die trainingsinduzierten lokalisierten Veränderungen der kortikalen Faltung von einem ähnlichen Muster vergleichbarer struktureller Veränderungen zwischen ROIs innerhalb der Regionen begleitet wurden. In Zukunft sind weitere Forschungen erforder-lich, um diese Ergebnisse zu wiederholen und zu validieren sowie um trainingsinduzierte topologische und topografische Veränderungen anhand einer breiteren Palette von Metri-ken und Eigenschaften zu untersuchen.The accelerating global aging process and the fact that cognitive abilities deteriorate with age, which has a significant impact on the quality of life of older adults, particularly those with age-related disorders (e.g., cognitive impairment, dementia), all point to an urgent need for approaches to protect and enhance cognitive abilities, as well as studies of the neural substrates of aging-related changes and neuroplasticity. Since working memory (WM) has been assumed to be the fundamental source of age-related cognitive impair-ments in a variety of cognitive abilities, working memory training (WMT) has become a hot topic as well as a popular approach. Previous studies have established that working memory training (WMT) improves cognitive performance. However, the specific effects, as well as the underlying neurobiological mechanisms, remain a matter of controversy. The purpose of this thesis is to investigate WMT-induced neural structural plasticity at multiple levels together with the behavioral effects of WMT. In study one, we investigated the topographic changes of grey matter morphology due to WMT by combining four structural metrics (i.e., cortical thickness (CT), cortical volume (CV), cortical surface area (CSA), and local gyrification index (LGI)) as well as subcortical volumes. Specifically, 59 healthy volunteers between the ages of 50 and 65 were randomly assigned to either an adaptive or a non-adaptive intervention. All participants underwent neuroimaging as well as cognitive testing before and after the 8-week intervention. Four cortical metrics at ver-tex level and seven subcortical volumes, as well as global mean cortical thickness, were calculated before and after the intervention. The most important finding was that the adap-tive WMT group showed greater increases in cortical folding in bilateral parietal regions in comparison to the active control group who performed the non-adaptive intervention. The results indicate that structural changes due to adaptive WMT in WM related regions, particularly parietal regions, may facilitate the processing of a higher WM load. In addi-tion, the cortical folding might be the most relevant and plastic feature of WM and learn-ing, reflecting WMT effects more than other metrics. Based on the findings of study one, we further asked whether the training-induced effects of WMT in cortical folding at vertex-level are accompanied by topological changes. To this end, study two investigated network-level plasticity due to WMT by using the struc-tural covariance (SC) approach based on the same samples. Gyrification based SC matri-ces for each group before and after training, together with longitudinal gyrification SC matrices, were constructed. Within each group, the LGI-based SC analysis revealed no evidence of WMT-induced changes in cortical-cortical connections, either in the WMT or the active control groups. The results of the longitudinal SC analysis (uncorrected p < 0.005) revealed that the training induced changes of cortical folding intensity showed sig-nificant difference between pairs of parietal regions as well as pairs of frontal regions. Overall, the combined findings of these two studies indicate that: firstly, WMT can pro-duce neural structural plasticity; secondly, cortical folding might be the most relevant and plastic feature of WM and learning, better reflecting the effects of WMT than other vertex-level indicators; and thirdly, the training induced localized changes in cortical folding were accompanied by the pattern of similar structural changes between ROIs within the regions. In the future, more research is required to replicate and validate these findings, as well as to investigate training-induced topological and topographic changes using a broader set of metrics and properties

    Cerebrovascular dysfunction in cerebral small vessel disease

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    INTRODUCTION: Cerebral small vessel disease (SVD) is the cause of a quarter of all ischaemic strokes and is postulated to have a role in up to half of all dementias. SVD pathophysiology remains unclear but cerebrovascular dysfunction may be important. If confirmed many licensed medications have mechanisms of action targeting vascular function, potentially enabling new treatments via drug repurposing. Knowledge is limited however, as most studies assessing cerebrovascular dysfunction are small, single centre, single imaging modality studies due to the complexities in measuring cerebrovascular dysfunctions in humans. This thesis describes the development and application of imaging techniques measuring several cerebrovascular dysfunctions to investigate SVD pathophysiology and trial medications that may improve small blood vessel function in SVD. METHODS: Participants with minor ischaemic strokes were recruited to a series of studies utilising advanced MRI techniques to measure cerebrovascular dysfunction. Specifically MRI scans measured the ability of different tissues in the brain to change blood flow in response to breathing carbon dioxide (cerebrovascular reactivity; CVR) and the flow and pulsatility through the cerebral arteries, venous sinuses and CSF spaces. A single centre observational study optimised and established feasibility of the techniques and tested associations of cerebrovascular dysfunctions with clinical and imaging phenotypes. Then a randomised pilot clinical trial tested two medications’ (cilostazol and isosorbide mononitrate) ability to improve CVR and pulsatility over a period of eight weeks. The techniques were then expanded to include imaging of blood brain barrier permeability and utilised in multi-centre studies investigating cerebrovascular dysfunction in both sporadic and monogenetic SVDs. RESULTS: Imaging protocols were feasible, consistently being completed with usable data in over 85% of participants. After correcting for the effects of age, sex and systolic blood pressure, lower CVR was associated with higher white matter hyperintensity volume, Fazekas score and perivascular space counts. Lower CVR was associated with higher pulsatility of blood flow in the superior sagittal sinus and lower CSF flow stroke volume at the foramen magnum. Cilostazol and isosorbide mononitrate increased CVR in white matter. The CVR, intra-cranial flow and pulsatility techniques, alongside blood brain barrier permeability and microstructural integrity imaging were successfully employed in a multi-centre observational study. A clinical trial assessing the effects of drugs targeting blood pressure variability is nearing completion. DISCUSSION: Cerebrovascular dysfunction in SVD has been confirmed and may play a more direct role in disease pathogenesis than previously established risk factors. Advanced imaging measures assessing cerebrovascular dysfunction are feasible in multi-centre studies and trials. Identifying drugs that improve cerebrovascular dysfunction using these techniques may be useful in selecting candidates for definitive clinical trials which require large sample sizes and long follow up periods to show improvement against outcomes of stroke and dementia incidence and cognitive function

    Taylor University Catalog 2023-2024

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    The 2023-2024 academic catalog of Taylor University in Upland, Indiana.https://pillars.taylor.edu/catalogs/1128/thumbnail.jp

    Artificial Intelligence for Cognitive Health Assessment: State-of-the-Art, Open Challenges and Future Directions

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    The subjectivity and inaccuracy of in-clinic Cognitive Health Assessments (CHA) have led many researchers to explore ways to automate the process to make it more objective and to facilitate the needs of the healthcare industry. Artificial Intelligence (AI) and machine learning (ML) have emerged as the most promising approaches to automate the CHA process. In this paper, we explore the background of CHA and delve into the extensive research recently undertaken in this domain to provide a comprehensive survey of the state-of-the-art. In particular, a careful selection of significant works published in the literature is reviewed to elaborate a range of enabling technologies and AI/ML techniques used for CHA, including conventional supervised and unsupervised machine learning, deep learning, reinforcement learning, natural language processing, and image processing techniques. Furthermore, we provide an overview of various means of data acquisition and the benchmark datasets. Finally, we discuss open issues and challenges in using AI and ML for CHA along with some possible solutions. In summary, this paper presents CHA tools, lists various data acquisition methods for CHA, provides technological advancements, presents the usage of AI for CHA, and open issues, challenges in the CHA domain. We hope this first-of-its-kind survey paper will significantly contribute to identifying research gaps in the complex and rapidly evolving interdisciplinary mental health field

    Investigating the role of enhancer-mediated gene expression in the human brain and its potential contribution to psychiatric disorders

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    Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two neuropsychiatric conditions with variable times of onset and are influenced by both genetic and environmental factors. Genome-wide association studies (GWASs) have led to the identification of numerous genetic loci common to both these disorders, however our understanding remains far from complete, with many clinical cases without a genetic cause. While increasing the statistical power of genome-wide association studies (GWASs) to find additional risk variants could rule-in or rule out rare cases of ASD and SCZ, this presently remains a difficult task. Furthermore, the biological functions for genetic susceptibility loci remains poorly understood, particularly for more-recent discoveries of loci devoid of gene bodies. On the other hand, recent biotechnological developments have made it possible to conduct high-resolution experimental measurements of the three-dimensional architecture of the genome, including enhancer-promoter interactions (EPIs). Such data have been used to connect GWAS risk variants to their potential target genes which, in turn, provide insights into underlying molecular mechanisms and cellular processes. The functions of enhancer-promoter interactions in controlling gene expression programmes is crucial to how implicated genes mediate neurological function and disease. Yet, knowledge on enhancer-promoter interactions remains to be used in conjunction with GWAS data, particularly on such data from specific brain cell types, which may be useful to uncover the biological underpinnings of psychiatric conditions. This thesis examines the role of enhancer-mediated gene expression in the human brain and its potential contribution to psychiatric conditions. In Chapter 2, I report on the identification of significant chromosomal interactions from studies of brain Hi-C data generated from neuronal and glial cells, with the goal to investigate the impact of EPIs genome-wide, as well as to provide a template for an in-depth understanding of how EPIs impact transcriptional regulation. In the Chapter 3, I discuss a novel approach integrating Activity by Contact (ABC) and gene set enrichment analyses of GWAS data in two steps. In the first step, ABC is used to predict enhancer-gene regulatory interactions in a given cell type (e.g., glial cells, neurons). Secondly, Hi-C coupled multi-marker analysis of genomic annotation (H-MAGMA) is used to assign the SNPs located in the regulatory regions identified by ABC to each gene and calculate gene-level association p-values. I applied this novel framework (ABC-HMAGMA) to GWAS data from SCZ and ASD, to identify novel SCZ and ASD trait-associated genes and molecular pathways. In Chapter 4, I have evaluated a potential novel mechanism for the regulation of enhancer activity within cells. I hypothesized that, in addition to its known roles in DNA replication and transcription, Topoisomerase I may regulate enhancer activity in brain cells. To test this hypothesis, I employed RNA-seq and transient transcriptome sequencing (TT-seq) data, a method that enriches for short-lived enhancer derived RNAs. These data showed that Topoisomerase I inhibition leads to significant changes in eRNA expression and offers evidence that such changes are relevant to the homeostatic functions for Top 1 in cellular gene expression regulation
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