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Publication Place Identity Variation across Ages in a Hyper-Segregated Neighborhood: Wendell Phillips Neighborhood, Kansas City Missouri(Environmental Design Research Association, 2024-06-21)This study explores and comprehends the intricacies of place identity within Wendel Phillips, a Kansas City, Missouri neighborhood established in unjust socio-economic conditions and racial segregation. Place identity embodies the subjective and emotive ties individuals or communities forge with a specific geographic location, encompassing personal meanings, emotions, memories, and symbolic affiliations. These elements significantly shape one's sense of belonging, attachment, and identification with a particular environment, intertwining with the construction of a distinct identity closely linked to the attributes of that place. The research methodology involved qualitative methods, including unstructured interviews, and mapping exercises, engaging 20 residents from diverse age groups (above 18 years old), genders, and residency durations within Wendel Phillips. This comprehensive approach aimed to straighten out how demographic variances influence the perception of identity within a shared environment characterized by similar challenges and aspirations. By amplifying the voices of the community, this study seeks to spotlight multifaceted perspectives, diverse familiarities, and future visions, ultimately proposing inclusive changes. Place identity plays a pivotal role in an individual's self-concept and their connection with the broader world, fostering a profound sense of belonging to a specific place or community. By scrutinizing a spectrum of personal perceptions across different ages and genders within the neighborhood, this research endeavors to reshape the prevailing narrative from suppression to optimism for the future. It emphasizes the profound impact of stories on shaping present perceptions and empowering the potential trajectory of the neighborhood. Recognizing the evolutionary nature of identity with perceptions, this study challenges the subjective essence of place identity. It sheds light on residents proposed future changes, offering a glimpse into transformative pathways within the community. By embracing diverse narratives, this research underlines the dynamic nature of identity within a shared space and the implications for future development. In essence, this study not only unties the complexities of place identity within a marginalized community but also advocates for a more inclusive and empowered future. By acknowledging and amplifying diverse perspectives, it paves the way for understanding the nuanced interplay between individual identities and the environment, envisioning a neighborhood that thrives on collective narratives and inclusive transformations.Publication The RNA-binding Protein HuR in Cancer Immune Evasion: Mechanisms and Therapeutic Implications(University of Kansas, 2023-01-01)RNA-binding protein (RBP) HuR is upregulated in multiple types of cancer and the elevated HuR is associated with high-grade tumors and poor clinical outcomes. HuR forms a complex network of interactions with target mRNAs through the recognition and binding to the adenylate-uridylate-rich elements (AU-rich elements; AREs) in their 3′-untranslated region (3′-UTR). By regulating the expression of proto-oncogenes, cytokines, and other regulatory proteins involved in various cancer hallmarks, HuR promotes tumorigenesis and cancer progression.Cancer immunotherapy, particularly the immune checkpoint blockade (ICB) represents a revolutionary advance in cancer treatment. However, only a subset of patients responds to ICB. Response rates to ICB in breast cancer, lung cancer, and prostate cancer patients are notably low. ICB targeting Programmed cell death-1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) has greatly improved clinical outcomes in diverse human cancers. However, a more thorough understanding of the mechanisms underlying low immunogenicity in these tumors is crucial to address remaining issues, including the low objective response rates in patients.In this study, we investigate the involvement of HuR in T cell activation and demonstrated that HuR knockout in cancer cells reduced PD-L1 proteins and enhanced T cell activation. We identified HuR as a novel regulator of PD-L1 and CD147 by directly binding to the 3′-UTR of their mRNA, thereby promoting their stability. Given the immunosuppressive functions of PD-L1 and CD147 in cancer, we hypothesized that functional inhibition of HuR could be a promising approach to enhance ICB efficacy. We repurposed the anti-helminthic drug niclosamide as a HuR inhibitor and discovered that it decreased PD-L1 protein levels and glycosylation by inhibiting the nucleo-cytoplasmic translocation of HuR. Niclosamide enhanced T cell-mediated killing of cancer cells and significantly improved the efficacy of anti-PD-1 immunotherapy in breast and lung syngeneic animal tumor models. To further explore the role of HuR in cancer immune evasion through CD147 regulation, we developed a HuR-specific small molecular inhibitor, KH-39, which disrupts the interaction between HuR and its target mRNAs. KH-39 effectively inhibits CD147 expression and its associated cytokine IL-6. We established a combination strategy using HuR inhibitor KH-39 and anti-PD-1 antibody to enhance the ICB response rate in a murine breast cancer model. The combination approach demonstrated substantial tumor growth inhibition and significantly improved overall survival compared to the single-agent treatments. In conclusion, this dissertation research expands our understanding of the biological role of HuR in tumor immune evasion. It provides a strong proof-of-principle of targeting HuR to modulate its downstream signaling to enhance the response of ICB immunotherapy, particularly in immune “cold” cancers.Publication British History is Their History: Britain and the British Empire in the History Curriculum of Ontario, Canada and Victoria, Australia 1930-1975(FahrenHouse, 2017)This article investigates the evolving conceptions of national identity in Canada and Australia through an analysis of officially sanctioned history textbooks in Ontario, Canada and Victoria, Australia. From the 1930s until the 1950s, Britain and the British Empire served a pivotal role in history textbooks and curricula in both territories. Textbooks generally held that British and imperial history were crucial to the Canadian and Australian national identity. Following the Second World War, textbooks in both Ontario and Victoria began to recognize Britain’s loss of power, and how this changed Australian and Canadian participation in the British Empire/Commonwealth. But rather than advocate for a complete withdrawal from engagement with Britain, authors emphasized the continuing importance of the example of the British Empire and Commonwealth to world affairs. In fact, participation in the Commonwealth was often described as of even more importance as the Dominions could take a more prominent place in imperial affairs. By the 1960s, however, textbook authors in Ontario and Victoria began to change their narratives, de-emphasizing the importance of the British Empire to the Canadian and Australian identity. Crucially, by the late 1960s the new narratives Ontarians and Victorians constructed claimed that the British Empire and national identity were no longer significantly linked. An investigation into these narratives of history will provide a unique window into officially acceptable views on imperialism before and during the era of decolonization.Publication Combining the Benefits of Biotin–Streptavidin Aptamer Immobilization with the Versatility of Ni-NTA Regeneration Strategies for SPR(MDPI, 2024-04-27)The high affinity of the biotin–streptavidin interaction has made this non-covalent coupling an indispensable strategy for the immobilization and enrichment of biomolecular affinity reagents. However, the irreversible nature of the biotin–streptavidin bond renders surfaces functionalized using this strategy permanently modified and not amenable to regeneration strategies that could increase assay reusability and throughput. To increase the utility of biotinylated targets, we here introduce a method for reversibly immobilizing biotinylated thrombin-binding aptamers onto a Ni-nitrilotriacetic acid (Ni-NTA) sensor chip using 6xHis-tagged streptavidin as a regenerable capture ligand. This approach enabled the reproducible immobilization of aptamers and measurements of aptamer–protein interaction in a surface plasmon resonance assay. The immobilized aptamer surface was stable during five experiments over two days, despite the reversible attachment of 6xHis-streptavidin to the Ni-NTA surface. In addition, we demonstrate the reproducibility of this immobilization method and the affinity assays performed using it. Finally, we verify the specificity of the biotin tag–streptavidin interaction and assess the efficiency of a straightforward method to regenerate and reuse the surface. The method described here will allow researchers to leverage the versatility and stability of the biotin–streptavidin interaction while increasing throughput and improving assay efficiency.Publication Potent small molecule inhibitors against the 3C protease of foot-and-mouth disease virus(American Society for Microbiology, 2024-03-11)Foot-and-mouth disease (FMD) is one of the most devastating diseases of livestock which can cause significant economic losses, especially when introduced to FMD-free countries. FMD virus (FMDV) belongs to the family Picornaviridae and is antigenically heterogeneous with seven established serotypes. The prevailing preventive and control strategies are limited to restriction of animal movement and elimination of infected or exposed animals, which can be potentially combined with vaccination. However, FMD vaccination has limitations including delayed protection and lack of cross-protection against different serotypes. Recently, antiviral drug use for FMD outbreaks has increasingly been recognized as a potential tool to augment the existing early response strategies, but limited research has been reported on potential antiviral compounds for FMDV. FMDV 3C protease (3Cpro) cleaves the viral-encoded polyprotein into mature and functional proteins during viral replication. The essential role of viral 3Cpro in viral replication and the high conservation of 3Cpro among different FMDV serotypes make it an excellent target for antiviral drug development. We have previously reported multiple series of inhibitors against picornavirus 3Cpro or 3C-like proteases (3CLpros) encoded by coronaviruses or caliciviruses. In this study, we conducted structure-activity relationship studies for our in-house focused compound library containing 3Cpro or 3CLpro inhibitors against FMDV 3Cpro using enzyme and cell-based assays. Herein, we report the discovery of aldehyde and α-ketoamide inhibitors of FMDV 3Cpro with high potency. These data inform future preclinical studies that are related to the advancement of these compounds further along the drug development pathway. IMPORTANCE Food-and-mouth disease (FMD) virus (FMDV) causes devastating disease in cloven-hoofed animals with a significant economic impact. Emergency response to FMD outbreaks to limit FMD spread is critical, and the use of antivirals may overcome the limitations of existing control measures by providing immediate protection for susceptible animals. FMDV encodes 3C protease (3Cpro), which is essential for virus replication and an attractive target for antiviral drug discovery. Here, we report a structure-activity relationship study on multiple series of protease inhibitors and identified potent inhibitors of FMDV 3Cpro. Our results suggest that these compounds have the potential for further development as FMD antivirals.
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