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Biomechanical Properties Of Breast Tumor Spheroids Measured By Brillouin Microscopy
No full textAccording to the World Health Organization, breast cancer is the most prevalent cancer worldwide as of 2023. It has been evidenced that breast cancer progression is regulated by multiple factors. Among them, biomechanics plays an important role through the mechanism of mechanotransduction. In comparison to healthy cells, tumor cells are softer and more flexible to adjust their stiffness in response to mechanical cues from their microenvironment. While the biomechanics of tumor cells has been extensively studied in vitro, most of the mechanical measurements are conducted in 2D culturing conditions, which cannot recapitulate the important features of 3D physiological tissue. Tumor spheroids cultured in 3D microenvironments is evidenced to be more physiologically relevant than 2D cultures. However, existing techniques for measuring mechanical properties cannot probe 3D biomechanics because they are generally contact-based and invasive. The purpose of this study was to reveal the mechanical evolution of cancer cells within multicellular spheroids by using an innovative all-optical technique, Brillouin microscopy. First, this work has validated the measured Brillouin modulus via comparison with an existing contact-based technique, namely atomic force microscopy, with single cells. Next, the mechanical properties of the spheroids were monitored by Brillouin microscopy as they grow, allowing quantification of the different mechanical behaviors observed in healthy and tumor spheroids. This research provides direct evidence regarding the biomechanics of cancer cells during tumor growth in 3D, which is an important complement to the existing knowledge based on 2D cell cultures. Our findings demonstrate significant differences in the Brillouin shift between MCF10A and MCF10CA1h when cultured in 3D matrices. This suggests that the mechanical properties measured via Brillouin microscopy could serve as a promising biomarker for assessing the relative metastatic potential of both non-tumorigenic and malignant mammary epithelial spheroids, and potentially across various cancer cell lines. The outcome of this work can potentially serve as a new method to evaluate the performance of cancer therapies and drug screening in both preclinical and clinical studies for cancer prevention
Novel Regulators Of Small G Proteins In The Pancreatic Beta Cell
Get PDFRegulation of small GTPases within the pancreatic beta cell is a highly complex and coordinated sequence of protein interactions and post translational modifications. Various families participate in the physiological secretion of insulin in roles ranging from cytoskeletal reorganization to secretory vesicle priming and docking. However the regulatory partners of GTPase function, while studied broadly, lack vital information relating to smgGDS, a protein chaperone of small GTPases to and from the prenylation machinery, and RhoGDI function. Herein these studies are aimed to further our understanding of GTPase regulation and alterations that occur during metabolic stress (glucotoxicity) and related beta cell dysfunction.Data presented show, for the first time, the expression of both smgGDS splice variants within multiple insulin secreting cell lineages and that siRNA mediated depletion of smgGDS significantly decreases glucose-, calcium-, and cAMP-mediated forms of stimulatory insulin secretion. Studies have also presented novel information regarding the expression and nuclear localization of RhoGDI proteins within numerous insulin secreting cell types and that only RhoGDIβ shows an appreciable increase in expression during prolonged periods of metabolic stress, in both whole cell lysates and the nuclear fraction. Previous studies have implicated the cleavage of RhoGDIβ under certain cellular stress conditions, and data presented here show that prolonged exposure to elevated glucose results in increased RhoGDIβ cleavage and translocation of this fragment to the nuclear fraction. These studies have reported novel and significant findings regarding the role of smgGDS in insulin secretion from the pancreatic beta cell and physiologically relevant alterations in the expression and cleavage of RhoGDIβ under prolonged conditions of metabolic stress
Essays In Covid-19 Consumption Decisions
No full textThe COVID-19 pandemic prompted widespread lifestyle changes across the United States. Leveraging SafeGraph\u27s foot traffic dataset, Patterns, this study assesses the impact of these policies on visits to fast-food outlets, dine-in restaurants, and grocery stores at the Census Tract level from January 2019 to May 2022. Employing a two-way fixed effects difference-in-differences model, significant decreases in visits to all food establishments post-March 2020 were observed, particularly pronounced for restaurants and fast-food outlets, with effects persisting beyond the pandemic. Notably, there was a shift towards increased grocery store visits. Additionally, this dissertation investigates how COVID-19 disruptions influenced consumers\u27 grocery purchasing behaviors. Analyzing Nielsen\u27s Consumer Panel dataset, households in counties with stay-at-home orders exhibited increased total spending on both healthy and unhealthy foods, alongside minor compositional changes in weekly purchases enduring beyond the pandemic\u27s initial phase. Moreover, variations in shopping behavior were observed based on household location, structure, and socioeconomic status. Finally, this dissertation examines the impact of alcohol to-go policies implemented by many states during the COVID pandemic. Despite no significant increase in restaurant or bar patronage, there is a notable 14.9% rise in drunk driving arrests following the policy implementation was observed
Leader Unethical Behavior And Employee Expediency: Exploring Meaning Depletion And The Moderating Role Of Neuroticism
No full textThis study examines the role of unethical leader behavior in promoting unethical employee behavior. Specifically, leveraging COR theory, I hypothesize that leader unethical pro-organizational behavior (LUPB) threatens the meaning individuals derive from their work, and that this is positively associated with expediency to conserve remaining resources. Furthermore, I argue that this effect is stronger for individuals high in neuroticism. This study utilizes a cross-sectional survey design (i.e., two timepoints, four weeks apart) to collect data from 351 participants. Results suggest that LUPB undermines the meaning employees derive from their work, but they do not support the hypothesis that this influences employee expediency. Results also do not support the moderating effect of neuroticism. A supplemental analysis, however, reveals a significant relationship between LUPB and both work meaningfulness and expediency as well as a significant moderating effect of neuroticism on the LUPB-work meaningfulness relationship. This research broadens the unethical leadership literature and can provide insights for organizations seeking to foster a more ethical work environment
Response Characterization And Prediction Of Uhpc Flat Plates Subjected To Perpendicular Axisymmetric Concentrated Loads
No full textA methodology is presented that accurately and consistently predicts the complete moment-curvature (M-χ) response of UHPC cross-sections. Furthermore, a computational framework is presented to characterize the response of UHPC flat plates subjected to perpendicular axisymmetric concentrated loads. The presented framework is concerned with the prediction of the complete flexural response and punching shear capacity of UHPC flat plates thus addressing two fundamental limit states related to the design of UHPC flat plates. Guidance is provided for how to convert continuous flat plates supported by discrete columns into isolated plates supported by a single column in terms of plate dimensions and boundary conditions. Such plates are then converted into circular plates for the purpose of obtaining the load-rotation (V-ψ) response of the plate. The response of the circular plate is then characterized by considering the kinematics and internal force distribution in a representative slice. This requires the provision of the M-χ response of representative strips of unit width. Once the complete flexural response is obtained, a nonlinear regression-based failure criterion is used to identify punching shear failures and distinguish them from flexural failures. A total of seven different methods, Level I to Level Vc, are presented to predict the V-ψ response of the reinforced UHPC (R-UHPC) plates. In addition, a regression based formulation is developed to predict the punching shear capacity of R-UHPC plates. The contribution of this study applies to the following three themes: 1) the development of an algorithm that is capable of supplying the entire M-χ response of UR- and R-UHPC cross-sections; 2) the development of a computational framework for obtaining the complete V-ψ relationship of a R-UHPC plate subjected to concentrated loads; and 3) the provision of a failure criterion, which together with the V-ψ response of the plate are used to determine the punching shear capacity of the plate. The accuracy of the exiting methodologies for predicting punching shear strength is evaluated using a database of 64 tested plates, 39 of which are reinforced and 25 are unreinforced. A total of 13 existing methodologies are evaluated in terms of their ability to accurately predict the punching shear capacity of UHPC plates, and they lead to average ratios of tested to predicted punching shear strength and coefficients of variation (CoV) that range from 0.50-2.42 and 36%-58%, respectively, suggesting an urgent need to develop more accurate and consistent methods. The proposed methods when applied to R-UHPC plates supply an average ratio of tested to predicted punching shear strength between 1.11-1.25 with 22.8-24.3% CoV, suggesting largely improved accuracy and consistency. Similarly, the predicted load versus rotation response of UHPC plates that exhibit a flexural failure is compared with the tested response leading to good agreement. A computer program iRes is developed to characterize the response and predict the punching shear capacity of UHPC plates
Distance In Topological Data Analysis
No full textData analysis has undergone a remarkable transformation in recent years, spurredby the explosion of data generated from diverse sources ranging from scientific experiments to social media interactions. Topological data analysis (TDA) is a recent field of applied mathematics that provides algebraic topology and computational geometry tools for inferring relevant information from possibly complex data. Persistent homology is a crucial concept in TDA because it identifies and tracks topological features across multiple resolutions, thereby providing a robust summary of shape and structure in the data. It turns out that the classical Hausdorff distance is unsuitable for comparing simplicial complexes, prompting the need for a revised notion of distance on the space of finite sets of simplices in R^d. This dissertation is centered around a simplicial complex metric. By focusing on individual abstract simplicial complexes before they are incorporated into filtered complexes, this work contributes to the preprocessing and representation of data before persistence is applied. Moreover, noting that F_2-homology cycle representatives may be described as simplicial subcomplexes, we also discuss the notion of optimal homology bases as a concise summary of homology present in a simplicial complex. By computing distances between individual simplicial complexes, this work offers a means to assess the similarity of topological features encoded by homology cycles
Studies On Electron Transport In Ordered Mono- And Multilayered Films Of New Metal Containing (fe, Co, Ru) Amphiphiles, Hydrophobes And Hierarchical Self Assemblies
No full textThis dissertation research focused on two main objectives: (i) developing newly substituted redox-active metallosurfactants and hydrophobic metal complexes for current rectification, and (ii) creating a new immobilization strategy to form hierarchical self-assembled bilayers on a conductive substrate. These bilayers, which include a chromophore and a catalyst, are intended for use in water-splitting catalysis. The first objective was probed based on the hypothesis that halogen substitution of the ligand framework can reduce the electron density around the metal center of a complex thereby reducing the Au Fermi-SOMO that will facilitate directional electron transport. Furthermore, it was hypothesized that the redox activity and film formation ability due to bent spatial geometry by a hydrophobic metal complex may promote directional electron transport. For the second objective, we hypothesized that the introduction of alkoxy chains in a catalyst would lead to more stable chromophore/catalyst bilayer structures due to the incorporation of stronger dipole interactions between the alkoxy groups on the catalyst and the alkyl moieties on the anchoring chromophore.As such, new iodo-substituted phenolate-based amphiphilic and redox-active amino catechol-based hydrophobic iron(III) complexes were synthesized and characterized for current rectification studies. On the other hand, alkyl and alkoxy-substituted amido-based cobalt(III) complexes were designed, synthesized, and characterized. These water oxidation catalysts were used together with ruthenium(II) bpy-based chromophore synthesized by Prof. Javier Concepcion to develop and characterize self-assembled bilayers for future catalytic studies. First, we evaluated the effects of peripheral changes and the development of 3d5 FeIII systems where iodo groups replace the usual tert-butyl groups attached to phenylenediamine-bridged phenolate donors. Two new metallosurfactants were designed, namely [FeIII(L1)Cl] (1) and [FeIII(L2)Cl] (2), where 1 incorporates shorter hydrophilic alkoxy chains than 2. These species had their electronic and electrochemical properties evaluated by experimental and computational methods. We also considered ancillary changes, such as subphase polarity effects on their interfacial properties of Pockels-Langmuir monolayer films on water and Langmuir-Blodgett monolayer films on gold electrodes, evaluated by multiple surface-dedicated methods and probed for directional electron transfer in Au|LB|Au and EGaIn|LB|Au junctions, prior to comparison to the previously published t-Bu substituted standard [FeIII(LtBu)Cl] (3). These modifications led to significant modulation of metal-based SOMO energy levels towards the Fermi energy levels of the electrode from 1.0 eV in complex 3 to ca. 0.5 eV in complex 1 and 2, which resulted in better currents observed than those for complex 3. To further explore the possible modulation of the Fermi/SOMO/HOMO gaps, we synthesized and structurally characterized an unprecedented hydrophobic 3d5 HSFeIII complex with o-iminobenzosemiquinonate and o-imino-phenolate derivatives, designated as [Fe(L)(Cl)] (1), both in solid state and solution. The electronic structure and redox behavior of this species were thoroughly investigated through experimental techniques and density functional theory (DFT) calculations, revealing the availability of energetically accessible ligand-based molecular orbitals relevant for directional electron transport. This species successfully forms stable Pockels–Langmuir films at the air|water interface, regardless of its hydrophobic nature enabling the deposition of thin films on gold and eutectic gallium indium electrodes to create nanoscale Au|LB|Au and EGaIn|LB|Au junctions for current-voltage (I/V) measurements. Remarkably, this species demonstrated a proposed rare asymmetric or unimolecular electron transport with a maximum rectification ratio of 32, attributed to possible electron tunneling through the HOMO and LUMO of the aminocatechol moiety. To probe the new catalyst immobilization strategy, we designed two CoIII-based molecular catalyst candidates, namely [CoIIIL1(pyrr)2]ClO4 (Co1) and [CoIIIL2(pyrr)2]ClO4 (Co2) where L1 and L2 are the respective deprotonated forms of N,N′-[4,5-bis(dodecyloxy)-1,2-phenylene]dipicolinamide, and N,N′-[4,5-bis(methoxyethoxy)-1,2-phenylene]dipicolinamide and characterized their electrochemical, electronic, and film formation properties. Species Co1 and Co2 were deposited by means of a hierarchical self-assembled strategy in which an anchor molecule such as octylphosphonic acid (OPA) or the chromophoric [RuII(bpyPO3H)2(bpyC7)]Cl2 (Ru) was deposited onto conductive FTO prior to receiving the cobalt species. Four hierarchical films were obtained, namely, FTO|OPA-Co1, FTO|OPA-Co2, FTO|Ru-Co1 and FTO|Ru-Co2, and the role of dipole-dipole interactions between anchor and catalyst candidate was assessed. These newly-synthesized hierarchical films were characterized by a host of surface-specific methods that include X-ray photoelectron spectroscopy, spectroscopic ellipsometry, X-ray fluorescence, and contact angle, thus enabling an unprecedented level of analysis. Compared to the weak C—H van der Waals interactions exhibited by Co1, the presence of alkoxy chains in Co2 ensures stronger dipole-dipole interactions with the alkyl chain of the anchors due to O–H formation. The persistence of their redox properties, which include metal oxidation and directionality of electron transport, were probed, suggesting direct relevance to catalytic processes such as water oxidation. This dissertation research presented new classes of substituted bisphenolate, aminocatechol, and amido ligand-based systems and their iron(III), and cobalt(III) complexes, that exhibit amphiphilic or hydrophobic and redox properties being merged to facilitate directional electron transport. This dissertation project facilitated the understanding of structural, electronic, redox, spatial geometric, and interfacial properties of different classes of metal complexes and their specific roles in electron transport behavior determined from electrical property studies. Furthermore, this dissertation facilitated the understanding of a new strategy for immobilizing molecular water-splitting catalysts on conductive substrates using phosphonated anchors like octylphosphonic acid and phosphonated ruthenium(II) bpy-based chromophores. The bilayers containing substrate|chromophore-catalyst showed electrochemical and structural stabilities in different media, suggesting the possible applications in water oxidation or reduction
How To Survive The Journey Into Qualitative Research: A Novice’s Adventure
No full textThe prospect of a college degree can be daunting to many. Even more so for many that lack financial security or emotional support from friends or family. First-generation students can feel this as well with no experiences to refer to, like an older sibling or parent that have been through this situation. Although I personally have not been directly affected by these situations, I have worked with and around several students that were. The application of this blended autoethnographic and storytelling method is intended to produce a tool for those needing some advice, tips, and lessons they are not likely to gain in a classroom. We all learn from experiences, thankfully not always our own, and this is a collection of personal learned lessons that will possibly save the reader some struggle and lost time. Due to the dynamic pace of change in this area, many of the resources mentioned within will be obsolete at publication, however the concepts will remain valid. The steps taken to achieve this place should be sufficient to enable the reader to expand into the new horizons yet to come
Aging Lives Matter: An Exploration Of Spirituality And Prayer In The Lives Of African American Older Adults
No full textAfrican American older adults are living longer, and research suggests that a high number of African American older adults rely on their spiritual leaders for guidance on their mental health. However, there are gaps in past research on the connection between spirituality, prayer, and mental health for African American older adults. The purpose of this study was to examine how African American older adults use spirituality and prayer to cope with life difficulties. The theory of gerotranscendence was used to guide the study. The qualitative methodology of phenomenological analysis was used to collect and analyze the data. The study consists of 24 African American older adults from Flint, Michigan who described their experiences with spirituality and prayer when coping with life difficulties. Data was collected during the height of the coronavirus (COVID-19) pandemic through phone interviews with analysis discovering 13 emergent themes, which included (a) relationship with spirituality; (b) power of prayer; (c) connection to God; (d) early childhood development; (e) power of believing; (f) personal experiences; (g) consistent prayer; (h) death of family/friends; (i) health issues/challenges; (j) relationship with God and church; (k) family/social network; (l) Flint water crisis survival; and (m) coronavirus pandemic resilience. The participants described the role of spirituality and prayer in their lives, how spirituality and prayer are connected to their coping skills, stressful life events that lead them to spirituality and prayer, and strategies they utilize to cope with stress or life difficulties. This research adds to the body of knowledge about African American older adults lived experiences with spirituality and prayer as they cope with difficulties in their lives. Social work practices will be informed by this research regarding increasing social work knowledge of African American older adults and enhancing services that promote a better quality of life for older adults
Scaffolding Activities Of Pseudodeacetylases
No full textHistone Deacetylase (HDAC) enzymes remove acetyl groups from acetyl-lysine containing substrate proteins to regulate numerous cellular events, such as cell cycle progression, apoptosis, and cell proliferation. The clear role of HDAC proteins in cancer has led the development of HDAC inhibitors as anticancer therapeutics. Among the eleven-metal dependent HDAC proteins, class IIa HDAC isoforms (HDAC4, 5, 7, and 9) are enzymatically inactive in deacetylation reactions, and are pseudodeacetylases, due to mutation of a catalytic Tyr to His. Instead, class IIa HDAC proteins regulate histone deacetylation through a multi-protein complex that includes nuclear receptor corepressor NCoR/SMRT and active HDAC3. This multi-protein complex allows class IIa HDAC proteins to act as scaffolds to recruit active HDAC3 for deacetylation of acetylated lysines. But, only HDAC4, HDAC5 and HDAC7 associate with NCoR-HDAC3, which suggests that the HDAC9 mechanism of function might be different. Even with this known mechanism, the purpose of the inactive catalytic domain of class IIa HDAC isoforms in the scaffolding activity is unknown. Hence, class IIa HDACs are hypothesized to be “reader” proteins that bind to acetylated lysine residues on target proteins to cause a downstream biological function. However, the roles of HDAC4, 5, 7, and 9 as readers are yet to be explored. Here, we focused on studying scaffolding activities of two pseudodeacetylases HDAC7 and HDAC9.Recent evidence from the Pflum lab showed that the inactive pseudo-catalytic site of HDAC7 acts as a “reader” that binds acetyllysine-containing protein clients to control transcription by disrupting scaffolding to active HDAC3-NCoR complex. While prior work focused on AR (androgen receptor), here ER-⍺ (estrogen receptor alpha) transcription factor also showed acetylation-dependent HDAC7-NCoR-HDAC3 binding. Further, physiologically relevant breast cancer cells demonstrated HDAC7-mediated gene expression corroborating the reader function via NCoR-HDAC3 complex. These data substantiate HDAC7 as a reader of acetylation adding further mechanistic insights into the epigenetic roles of HDAC7. In a second project, we focused on HDAC9, which is one of the poorly studied pseudodeacetylases. Based on the reader hypothesis, we aimed to identify active site binders, scaffolding mediators, and associate proteins of HDAC9 using SAHA-dependent binder trapping strategy. The proteomics analysis revealed many potential deacetylase substrates, reader mediators, and associate proteins of HDAC9. Even though validation of candidate SAHA-dependent binders identified from the proteomics analysis was challenging, we discovered a novel interaction between HDAC9 and BAG2 (BAG family molecular chaperone regulator 2) which was not reported previously. Future studies will unveil the biological significance of HDAC9-BAG2 interaction. In summary, this dissertation work provided further evidence to establish HDAC7 reader function, Also, work documented here conveyed potential interactors of HDAC9 which will facilitate future research to understand unanticipated epigenetic and non-epigenetic roles of HDAC9. Finally, these studies broaden the insights into pseudodeacetylase biology and would encourage further investigations to gain more knowledge on class IIa HDAC proteins