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Elucidating the Proteolytic Determinants of Flavivirus Infection
No full textFlaviviruses, recently renamed to orthoflaviviruses, are small, enveloped viruses with positive-sense, single-stranded RNA (ssRNA) genomes of about 11 kilobases. Upon cell entry and uncoating, the viral RNA (vRNA) is directly translated at the endoplasmic reticulum (ER) as a single polyprotein that is then processed by the viral and cellular proteases into 10 functional subunits, consisting of three structural proteins and seven nonstructural (NS) proteins. Among the NS proteins are NS2B and NS3, which form the viral protease complex. NS3 consists of a serine protease domain while NS2B is anchored to the ER and contains a cytoplasmic loop that serves as a cofactor required for the catalytic activity of the protease. The NS2B3 protease complex is responsible for all cytoplasmic cleavage events of the viral polyprotein, making it an essential protein complex with functions required for the viral lifecycle. Many studies have reported on the structure, function, and importance of the viral protease; however, the molecular determinants for flavivirus protease cleavage of intracellular substrates and how these factors affect viral fitness are unknown. In the first half of this work, we developed and validated a reporter platform that detects intracellular flavivirus protease activity. By introducing various modifications into our tractable reporter system, we identified two previously uncharacterized molecular determinants associated with flavivirus protease cleavage efficiency. Specifically, we found that the ER membrane proximity of the protease recognition motif of the substrate as well as its localization to distinct subdomains of the ER greatly affect cleavage efficiency by flavivirus proteases. To our knowledge, this work is the first characterization of molecular determinants for flavivirus protease activity outside of primary sequence specificity. In the second half of this work, we introduced relevant primary sequences into our reporter construct and found that each flavivirus protease processed the motif located at the NS4A|2K junction of the polyprotein with poor cleavage efficiency. Using our reporter system with live-cell imaging to investigate comparative cleavage kinetics, we observed a significant delay in the processing of the NS4A|2K junction motif during dengue virus (DENV) infection. Further, we found that increasing the rate of cleavage at the NS4A|2K junction within flavivirus infectious clones was deleterious to viral fitness. Subsequent experiments revealed that this detriment was attributed to the inhibition of viral replication possibly due to a restriction in replication organelle formation upon premature cleavage at the NS4A|2K junction. Collectively, these findings characterize the molecular determinants of flavivirus protease activity and uncover the impact of cleavage specificity on infection
Optic Nerve Head Remodeling In Experimental High Myopia
Get PDFMyopia is a global health concern, with projected estimates that nearly half of the world\u27s population will be myopic by 2050. While its refractive aspect can be corrected, the heightened susceptibility to sight-threatening comorbidities, particularly with high myopia, remains a challenge. Among these comorbidities, glaucoma is a major concern, with myopia recognized as an independent risk factor. However, the mechanistic link between myopia and glaucoma remains poorly understood. This dissertation investigates the multiscale remodeling changes in experimental high myopia and their potential implications for increased risk of glaucoma later in life. Using a multimodal approach, this dissertation investigates: (1) neural canal opening remodeling and thickness changes of peripapillary tissues during juvenile high myopia development, (2) the impact of sustained high myopia on peripapillary tissues from juvenile age until early adulthood, and (3) changes in retinal function, optic nerve axonal counts, and retinal proteomics during juvenile high myopia development. The findings of these studies revealed that juvenile experimental high myopia induces progressive asymmetric deformations of the neural canal opening and heterogeneous thinning of peripapillary tissues, where the retina was relatively protected. Furthermore, sustained negative lens wear into early adulthood induced progressive myopia in a subset of eyes, where profound choroidal thinning during early myopia development emerged as a potential biomarker for future chorioscleral thinning and myopia progression. Lastly, while retinal function and optic nerve axonal counts were preserved during the juvenile stage of myopia, retinal proteomics identified differential modulation of key molecular pathways that may serve to protect the retina against various myopia-induced insults. These findings advance our understanding of the myopia remodeling changes and may suggest mechanistic links between myopia and glaucoma. The observed asymmetric remodeling of the neural canal opening and peripapillary tissues may alter the biomechanical environment at the ONH, potentially increasing the risk of pathological ONH remodeling and subsequent glaucoma development later in life. Moreover, the identified retinal protective mechanisms may become exhausted with aging, thereby heightening susceptibility to neurodegenerative conditions such as glaucoma. Lastly, this work identifies a potential biomarker for predicting progressive myopia, thereby offering novel avenues for early intervention and targeted therapeutic strategies
Accuracy Of 3D Printed Models With Various Range Of Crowding Created By Dlp Printer With Different Designs Of Model Base
Get PDFObjective: Treatment planning and appliance fabrication depend on the accurate representation of dentition. Research on the accuracy of digital light processing (DLP) printed models with different base designs across various levels of dental crowding remains limited. This study aims to evaluate the fidelity of DLP printed models and the suitability of different base designs for representing dentition with mild, moderate, and severe crowding. Materials and Methods: The objective is to determine the optimal base designs for DLP-printed models to address varying degrees of dental crowding. A two-way ANOVA was used to compare root mean square (RMS) error across different base designs and levels of crowding. The null hypothesis proposed no significant differences in accuracy across different base designs and levels of crowding. Results: The results of the two-way ANOVA showed no significant differences in accuracy across different levels of crowding. There are statistically significant differences between the horseshoe base and both the posterior bar and ABO base designs. Furthermore, analysis of the interaction between base design and varying levels of crowding revealed a significant difference in cases of severe crowding. The horseshoe design performs poorly compared to both the posterior bar and ABO base. These findings suggest that base design is a critical factor in cases of severe crowding. iii By identifying the most suitable base designs for accurately representing crowded dentition, the research supports improved precision in 3D-printed dental models. It is important to note, however, that while statistical analysis revealed significant differences, a few micrometers of inaccuracy may not result in clinically significant discrepancies when fabricating orthodontics appliances. Minor deviations in the printed model dimensions are often within an acceptable range for clinical use and may not impact the overall efficacy of orthodontic treatment outcomes. Conclusions: In conclusion, DLP-printed models with ABO or posterior bar base designs showed superior accuracy, regardless of the degree of crowding. The horseshoe-shaped base exhibited reduced accuracy, particularly in severe crowding cases. These findings support the use of structured base designs. This study provides evidence-based recommendations for selecting base designs that can improve the accuracy of DLP printed models
Evaluating Multiparametric Imaging Biomarkers For Guiding Targeted Therapies In Her2+ Breast Cancer
No full textHuman epidermal growth factor receptor 2 positive (HER2+) breast cancer is a biologically diverse disease, in which intratumoral heterogeneity plays a significant role in tumor progression. Advanced medical imaging and image processing techniques offer the potential to noninvasively characterize the underlying intratumoral biology. Capturing these complex changes can allow for assessing therapeutic response and eventually guiding personalized therapeutic strategies. This work evaluates single and multiparametric imaging biomarkers to characterize tumor biology, identify treatment-induced changes, and predict response to targeted therapies. First, the utility of 3’-Deoxy-3’-[18F]Fluorothymidine positron emission tomography ([18F]FLT-PET) was assessed as a biomarker of proliferation for monitoring response to combined HER2 and poly-ADP-ribose polymerase (PARP) inhibition. Preclinical studies demonstrated that [18F]FLT-PET detected early changes in cellular proliferation before significant tumor volume alterations. A normalized proliferative threshold was established to isolate proliferative tumor tissue, improving the clinical applicability of proliferation-based response monitoring. Second, a multiparametric PET/MRI-based clustering approach was developed to define physiologically distinct intratumoral habitats. By integrating diffusion weighted (DW)-MRI, dynamic contrast-enhanced (DCE)-MRI, [18F]2-Fluoro-2-deoxy-D-glucose ([18F]FDG), and [18F]FLT-PET data, hierarchical clustering was used to identify treatmentiv induced changes, which include reductions in the volume of hypoxic-treatment responsive zones following trastuzumab therapy. The imaging habitats were found to have significant positive linear correlations with matched histological-based habitat clustering. These findings highlight the potential of multiparametric imaging to capture early response patterns with biological relevance before measurable volumetric changes occur. Finally, [89Zr]Zr-trastuzumab-PET was integrated with DW-MRI to characterize HER2 expression and cellular density in a cohort of metastatic HER2+ breast cancer patients. [89Zr]Zr-trastuzumab-PET uptake was evaluated and reported in normal tissue. Additionally, it was found to be significantly higher in lesions compared to contralateral normal tissue. This multimodal approach improved the predictive performance of HER2- targeted imaging and allowed for intratumoral heterogeneity assessment in brain metastases and lymph node lesions. Multiparametric imaging biomarkers serve as powerful tools for characterizing HER2+ breast cancer. They enable for the characterization of early treatment-induced alterations which can inform on treatment response. The integration of these imagingderived biomarkers into clinical workflows represents a significant step toward enhancing precision oncology and improving patient outcomes for HER2+ breast cancer
Molecular Imaging Of Triple-Negative Breast Cancer: Characterization And Modulation Of The Tumor Microenvironment
No full textTriple-negative breast cancer (TNBC) is an aggressive, heterogeneous subset of breast cancer which currently has no targeted therapies available due to lack of molecular therapeutic targets. Importantly, various radiopharmaceuticals can be imaged via positron emission tomography (PET) to quantify cellular and molecular features of the tumor microenvironment including glucose metabolism, receptor status, and immune activation. Somatostatin receptor subtype 2 (SSTR2) is G-protein coupled receptor overexpressed in neuroendocrine tumors (NETs) which can be imaged and targeted for theranostics via FDA-approved radiotherapy. SSTR2 expression is increased in hormone positive breast cancer but is expressed at low or variable levels in TNBC. However, histone deacetylase (HDAC) inhibitors have been shown to upregulate SSTR2 expression for NETs with low or variable basal expression. Our data demonstrate the ability of HDAC inhibitors to upregulate SSTR2 expression in TNBC at the transcriptional, translational, and functional levels. Model-dependent differences and epigenetic-induced changes in SSTR2 expression can be quantified non-invasively and monitored longitudinally via PET imaging. Despite recent additions of immunotherapy (IMT) to TNBC treatment regimens, there are no standardized biomarkers to identify which patients will respond well to this therapy. In addition, co-morbidities like obesity and type 2 diabetes (T2D) confound TNBC and are associated with a dysfunctional immune microenvironment, thereby decreasing immunotherapeutic efficacy and worsening overall survival for TNBC. Challenges exist in FDG PET imaging of IMT response including distinguishing true response from pseudo-progression, inflammation, and immune activation. Our data reveals GZP PET as a sensitive predictor of immunotherapy response in obese mice early in the course of treatment and prior to tumor volume changes. Our studies also show that T2D and obesity alter not only the tumor microenvironment, but also impact the immune landscape and glucose metabolism in systemic tissues. Repurposing clinically relevant molecular imaging techniques for TNBC can be used to personalize treatment approaches and greatly enhance therapeutic responses. This work utilizes molecular imaging to non-invasively characterize the TNBC tumor microenvironment to identify predictors of treatment response and modulate the TME to create targetable biomarkers for imaging and therapy
Reducing the Flash-Lag Effect Through Visual Rehearsal: Implications for Visual Training in Athletes
Get PDF2025 Spring Expo Poster Presentation Biological & Life Scienceshttps://digitalcommons.library.uab.edu/sp-expo/1058/thumbnail.jp
Effects of Caffeine Consumption on Anxiety Levels in College Students
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Warm-water Fish Gelatin Nanofibers Produced via Alternating Field Electrospinning
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From Campus to Community: Supporting Black Warrior Riverkeeper
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Flow without Fear: One Pad at a Time
Get PDF2025 Spring Expo Poster Presentation Service-Learninghttps://digitalcommons.library.uab.edu/sp-expo/1090/thumbnail.jp