6,795 research outputs found

    Undergraduate Catalog of Studies, 2023-2024

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    Graduate Catalog of Studies, 2023-2024

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    Converging organoids and extracellular matrix::New insights into liver cancer biology

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    Speech-based automatic depression detection via biomarkers identification and artificial intelligence approaches

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    Depression has become one of the most prevalent mental health issues, affecting more than 300 million people all over the world. However, due to factors such as limited medical resources and accessibility to health care, there are still a large number of patients undiagnosed. In addition, the traditional approaches to depression diagnosis have limitations because they are usually time-consuming, and depend on clinical experience that varies across different clinicians. From this perspective, the use of automatic depression detection can make the diagnosis process much faster and more accessible. In this thesis, we present the possibility of using speech for automatic depression detection. This is based on the findings in neuroscience that depressed patients have abnormal cognition mechanisms thus leading to the speech differs from that of healthy people. Therefore, in this thesis, we show two ways of benefiting from automatic depression detection, i.e., identifying speech markers of depression and constructing novel deep learning models to improve detection accuracy. The identification of speech markers tries to capture measurable depression traces left in speech. From this perspective, speech markers such as speech duration, pauses and correlation matrices are proposed. Speech duration and pauses take speech fluency into account, while correlation matrices represent the relationship between acoustic features and aim at capturing psychomotor retardation in depressed patients. Experimental results demonstrate that these proposed markers are effective at improving the performance in recognizing depressed speakers. In addition, such markers show statistically significant differences between depressed patients and non-depressed individuals, which explains the possibility of using these markers for depression detection and further confirms that depression leaves detectable traces in speech. In addition to the above, we propose an attention mechanism, Multi-local Attention (MLA), to emphasize depression-relevant information locally. Then we analyse the effectiveness of MLA on performance and efficiency. According to the experimental results, such a model can significantly improve performance and confidence in the detection while reducing the time required for recognition. Furthermore, we propose Cross-Data Multilevel Attention (CDMA) to emphasize different types of depression-relevant information, i.e., specific to each type of speech and common to both, by using multiple attention mechanisms. Experimental results demonstrate that the proposed model is effective to integrate different types of depression-relevant information in speech, improving the performance significantly for depression detection

    Isotope reconstructions of East Asian Monsoon behaviour across Glacial Terminations I and II from Lake Suigetsu, Japan (IAP2−18−54)

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    Understanding the response of the East Asian Monsoon to rising temperatures is crucial in light of recent anthropogenic climate change and the vulnerability of East Asia to future climatic hazards. However, East Asian Monsoon dynamics during warming periods in the late Quaternary are poorly understood, particularly on decadal to millennial timescales. Significant sources of this uncertainty are the spatially and temporally heterogeneous responses of the East Asian Monsoon to submillennial temperature fluctuations. The conflicting patterns observed in available reconstructions of East Asian Monsoon strength suggest that the teleconnections acting during these intervals were complex. Understanding the behaviours of the East Asian Monsoon by accounting for links to remote climatic perturbations allows for a more holistic understanding of deglacial climate changes. A means of tackling this ambiguity is by contributing well−dated, high−resolution records of East Asian Monsoon evolution spanning Glacial Terminations I and II (which typify accessible, contrasting examples of rapid global warming) to the growing network of reconstructions from across the region. The aim of this thesis is to deconvolve East Asian Monsoon evolution during the last two glacial terminations by utilising the unique hydrological distribution of East Asian Monsoon precipitation over Japan to reconstruct both seasonal modes of the system (i.e., the East Asian Winter Monsoon and East Asian Summer Monsoon). This aim is met by the construction of isotope−based, season−specific East Asian Monsoon records across Glacial Terminations I and II using materials from the Lake Suigetsu sediment cores. This thesis is comprised of four interconnected research papers, preceded by an introduction and succeeded by a summary of findings, discussion of relevance, suggestions for future work and conclusions. In the first research paper, we utilise extended contemporary monitoring of the stable isotope composition of precipitation, river water and lake water in the Lake Suigetsu catchment to understand the factors affecting these variables and aid robust interpretation of isotope−based proxy reconstructions from the Lake Suigetsu sediment cores. Our results show that the composition of precipitation was influenced by the dual East Asian Monsoon system, and that these signals were then transferred to the lake system where they were combined with secondary local influences on lake water composition. Based on our knowledge of late Quaternary catchment dynamics, these observations suggest that the palaeo−isotope composition of Lake Suigetsu was closely related to the East Asian Monsoon. In the second research paper, we examine the influence of remote climatic processes on the East Asian Winter Monsoon and East Asian Summer Monsoon in Japan during Glacial Termination I by reconstructing trends in the strength of each seasonal mode. This is achieved using oxygen isotope analysis of diatom silica and compound−specific hydrogen isotope analysis of n−alkanoic acids from the Lake Suigetsu sediment cores. Our results support distinctive seasonal behaviours of the East Asian Monsoon during Glacial Termination I, with evidence for East Asian Winter Monsoon weakening and East Asian Summer Monsoon strengthening. The East Asian Summer Monsoon also exhibited variations in strength which were synchronous with Antarctic temperature fluctuations after 16,000 years ago, which supports a temporally restricted climatic link between Japan and the Southern Hemisphere at this time. In the third research paper, we reconstruct the East Asian Summer Monsoon in Japan during Glacial Termination II, and contrast the findings to those from Glacial Termination I. The reconstruction presented in this chapter, which is based on compound−specific hydrogen isotope analysis of n−alkanoic acids, provides evidence for early East Asian Summer Monsoon strengthening followed by a gradual weakening phase with submillennial−scale variability. Comparison of this record to others derived from mainland China supports the assertion that East Asian Summer Monsoon behaviours during Glacial Termination II were spatially heterogenous. Additionally, the different evolutions of the East Asian Summer Monsoon during Glacial Terminations I and II indicate that the system operated distinctively under contrasting boundary conditions, although the new reconstructions from Japan were consistently more closely linked with Southern Hemisphere (Antarctic) temperatures than Northern Hemisphere (Greenlandic) temperatures during both intervals. The fourth research paper was motivated by a lack of an absolute chronology for the oldest (pre−50,000 years ago) parts of the Lake Suigetsu sediment cores (which includes Glacial Termination II). In this paper, we appraise the luminescence characteristics of the cores using rapid profiling techniques. These are employed across four key time periods in order to assess the application of these methods for the detection of local and environmental shifts, and to assess the suitability of the core materials for luminescence dating. We show that the luminescence characteristics of the cores were susceptible to a range of environmental perturbations, best illustrating local changes by using high−resolution contiguous sampling. The feasibility of future luminescence dating is supported by quantifiable luminescence signals, and first order approximate ages suggest that blue light optically stimulated luminescence dating of feldspar provides the most accurate and most practical assessment of burial age. This technique should be the subject of dating efforts in pursuit of refinements to the Suigetsu core chronology before 50,000 years ago. The findings of this thesis contribute to our collective knowledge of East Asian Monsoon behaviours during glacial terminations. Critically, they represent a geographical expansion of the regional high−resolution record network to include Japan. The value of this process is demonstrated by the decoupled evolutions of each seasonal mode during Glacial Termination I, and a remote link between Antarctic temperatures and East Asian Summer Monsoon evolution in Japan during Glacial Terminations I and II, which were hitherto unconstrained by high resolution analysis. These findings acknowledge and begin to rationalise spatial and temporal heterogeneities in East Asian Monsoon behaviours by comparison to other records. This work highlights the complexity of the East Asian Monsoon, and the value of long records from contrasting deglacial periods for a better comprehension of this system in the context of anthropogenic climate change

    Converging organoids and extracellular matrix::New insights into liver cancer biology

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    Primary liver cancer, consisting primarily of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is a heterogeneous malignancy with a dismal prognosis, resulting in the third leading cause of cancer mortality worldwide [1, 2]. It is characterized by unique histological features, late-stage diagnosis, a highly variable mutational landscape, and high levels of heterogeneity in biology and etiology [3-5]. Treatment options are limited, with surgical intervention the main curative option, although not available for the majority of patients which are diagnosed in an advanced stage. Major contributing factors to the complexity and limited treatment options are the interactions between primary tumor cells, non-neoplastic stromal and immune cells, and the extracellular matrix (ECM). ECM dysregulation plays a prominent role in multiple facets of liver cancer, including initiation and progression [6, 7]. HCC often develops in already damaged environments containing large areas of inflammation and fibrosis, while CCA is commonly characterized by significant desmoplasia, extensive formation of connective tissue surrounding the tumor [8, 9]. Thus, to gain a better understanding of liver cancer biology, sophisticated in vitro tumor models need to incorporate comprehensively the various aspects that together dictate liver cancer progression. Therefore, the aim of this thesis is to create in vitro liver cancer models through organoid technology approaches, allowing for novel insights into liver cancer biology and, in turn, providing potential avenues for therapeutic testing. To model primary epithelial liver cancer cells, organoid technology is employed in part I. To study and characterize the role of ECM in liver cancer, decellularization of tumor tissue, adjacent liver tissue, and distant metastatic organs (i.e. lung and lymph node) is described, characterized, and combined with organoid technology to create improved tissue engineered models for liver cancer in part II of this thesis. Chapter 1 provides a brief introduction into the concepts of liver cancer, cellular heterogeneity, decellularization and organoid technology. It also explains the rationale behind the work presented in this thesis. In-depth analysis of organoid technology and contrasting it to different in vitro cell culture systems employed for liver cancer modeling is done in chapter 2. Reliable establishment of liver cancer organoids is crucial for advancing translational applications of organoids, such as personalized medicine. Therefore, as described in chapter 3, a multi-center analysis was performed on establishment of liver cancer organoids. This revealed a global establishment efficiency rate of 28.2% (19.3% for hepatocellular carcinoma organoids (HCCO) and 36% for cholangiocarcinoma organoids (CCAO)). Additionally, potential solutions and future perspectives for increasing establishment are provided. Liver cancer organoids consist of solely primary epithelial tumor cells. To engineer an in vitro tumor model with the possibility of immunotherapy testing, CCAO were combined with immune cells in chapter 4. Co-culture of CCAO with peripheral blood mononuclear cells and/or allogenic T cells revealed an effective anti-tumor immune response, with distinct interpatient heterogeneity. These cytotoxic effects were mediated by cell-cell contact and release of soluble factors, albeit indirect killing through soluble factors was only observed in one organoid line. Thus, this model provided a first step towards developing immunotherapy for CCA on an individual patient level. Personalized medicine success is dependent on an organoids ability to recapitulate patient tissue faithfully. Therefore, in chapter 5 a novel organoid system was created in which branching morphogenesis was induced in cholangiocyte and CCA organoids. Branching cholangiocyte organoids self-organized into tubular structures, with high similarity to primary cholangiocytes, based on single-cell sequencing and functionality. Similarly, branching CCAO obtain a different morphology in vitro more similar to primary tumors. Moreover, these branching CCAO have a higher correlation to the transcriptomic profile of patient-paired tumor tissue and an increased drug resistance to gemcitabine and cisplatin, the standard chemotherapy regimen for CCA patients in the clinic. As discussed, CCAO represent the epithelial compartment of CCA. Proliferation, invasion, and metastasis of epithelial tumor cells is highly influenced by the interaction with their cellular and extracellular environment. The remodeling of various properties of the extracellular matrix (ECM), including stiffness, composition, alignment, and integrity, influences tumor progression. In chapter 6 the alterations of the ECM in solid tumors and the translational impact of our increased understanding of these alterations is discussed. The success of ECM-related cancer therapy development requires an intimate understanding of the malignancy-induced changes to the ECM. This principle was applied to liver cancer in chapter 7, whereby through a integrative molecular and mechanical approach the dysregulation of liver cancer ECM was characterized. An optimized agitation-based decellularization protocol was established for primary liver cancer (HCC and CCA) and paired adjacent tissue (HCC-ADJ and CCA-ADJ). Novel malignancy-related ECM protein signatures were found, which were previously overlooked in liver cancer transcriptomic data. Additionally, the mechanical characteristics were probed, which revealed divergent macro- and micro-scale mechanical properties and a higher alignment of collagen in CCA. This study provided a better understanding of ECM alterations during liver cancer as well as a potential scaffold for culture of organoids. This was applied to CCA in chapter 8 by combining decellularized CCA tumor ECM and tumor-free liver ECM with CCAO to study cell-matrix interactions. Culture of CCAO in tumor ECM resulted in a transcriptome closely resembling in vivo patient tumor tissue, and was accompanied by an increase in chemo resistance. In tumor-free liver ECM, devoid of desmoplasia, CCAO initiated a desmoplastic reaction through increased collagen production. If desmoplasia was already present, distinct ECM proteins were produced by the organoids. These were tumor-related proteins associated with poor patient survival. To extend this method of studying cell-matrix interactions to a metastatic setting, lung and lymph node tissue was decellularized and recellularized with CCAO in chapter 9, as these are common locations of metastasis in CCA. Decellularization resulted in removal of cells while preserving ECM structure and protein composition, linked to tissue-specific functioning hallmarks. Recellularization revealed that lung and lymph node ECM induced different gene expression profiles in the organoids, related to cancer stem cell phenotype, cell-ECM integrin binding, and epithelial-to-mesenchymal transition. Furthermore, the metabolic activity of CCAO in lung and lymph node was significantly influenced by the metastatic location, the original characteristics of the patient tumor, and the donor of the target organ. The previously described in vitro tumor models utilized decellularized scaffolds with native structure. Decellularized ECM can also be used for creation of tissue-specific hydrogels through digestion and gelation procedures. These hydrogels were created from both porcine and human livers in chapter 10. The liver ECM-based hydrogels were used to initiate and culture healthy cholangiocyte organoids, which maintained cholangiocyte marker expression, thus providing an alternative for initiation of organoids in BME. Building upon this, in chapter 11 human liver ECM-based extracts were used in combination with a one-step microfluidic encapsulation method to produce size standardized CCAO. The established system can facilitate the reduction of size variability conventionally seen in organoid culture by providing uniform scaffolding. Encapsulated CCAO retained their stem cell phenotype and were amendable to drug screening, showing the feasibility of scalable production of CCAO for throughput drug screening approaches. Lastly, Chapter 12 provides a global discussion and future outlook on tumor tissue engineering strategies for liver cancer, using organoid technology and decellularization. Combining multiple aspects of liver cancer, both cellular and extracellular, with tissue engineering strategies provides advanced tumor models that can delineate fundamental mechanistic insights as well as provide a platform for drug screening approaches.<br/

    UMSL Bulletin 2023-2024

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    The 2023-2024 Bulletin and Course Catalog for the University of Missouri St. Louis.https://irl.umsl.edu/bulletin/1088/thumbnail.jp

    Graduate Catalog of Studies, 2023-2024

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    UMSL Bulletin 2022-2023

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    The 2022-2023 Bulletin and Course Catalog for the University of Missouri St. Louis.https://irl.umsl.edu/bulletin/1087/thumbnail.jp
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