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CRISPR-CAS12 Nanoparticles Alter Macrophage Function to Improve Inflammation After Traumatic Brain Injury in Mice
No full textOne of the first physiological and cellular events after a traumatic brain injury (TBI) is inflammatory-driven progressive neurodegeneration. The major players in this process are the brain resident immune microglia/macrophage cells (MG/Ma), which release inflammatory cytokines to cause an excess amount of inflammation. However, the largest obstacle to current TBI treatment is the challenge of targeting these MG/Ma cells. We designed a lipid nanoparticle (LNP) that can overcome this problem by locally delivering a clustered regularly interspaced short palindromic repeats (CRISPR) gene editing system specifically targeting the mitogen-activated protein kinase 9 (MAPK9) gene to polarize resident MG/Ma from their proinflammatory to anti-inflammatory state.
First, the CRISPR technology was combined with the LNPs to create a CRISPR-LNP system that was conjugated to an ionized calcium-binding adapter molecule 1 (Iba-1) antibody to increase specificity to central nervous system macrophages. We investigated the delivery efficacy of the CRISPR-LNP to reach the injured brain by comparing intravenous or intranasal administration. Then, we used a standardized cortical impact device to inflict a traumatic brain injury in adult male C57BL/6J mice. The data was visualized and analyzed using an advanced in vivo imaging system (IVIS), immunofluorescence analysis, and immunohistochemical staining with in situ hybridization.
Intranasal administration of Iba-1Ab-CRISPR-LNP produced greater specificity in binding to the injury compared to systemic administration. IVIS indicated that systemic administration led to a more significant accumulation of LNPs in the injured cortex. We found that the treatment reduced MG/Ma activation indicated by a change in macrophage morphology consistent with a reduction in the quantity of pro-inflammatory MG/Ma cells. We also found a decrease in the number of pro-inflammatory cytokines (IL-1�� and TNF��) and TUNEL-positive cells following CRISPR-LNP treatment compared with the vehicle group after 1-day post-TBI.
Our results showed that the Iba-1Ab-CRISPR-LNP reduced the MG/Ma activation indicated by morphology changes and the quantity of apoptosis of all cells after TBI. This work lays the foundation for developing a specific transformational therapeutic approach for TBI patients
Lip Position Preferences as They Relate to Convexity and Divergence
No full textIntroduction: The aim of the present study was to assess lip position preferences as they relate to convexity and divergence. Of secondary interest were how sex, ethnicity, and age influenced these preferences.
Methods: A sample of 1000 internet users were asked to rank the relative attractiveness of a series of modified 3D facial profiles with differing lip projections. One Caucasian male served as the model, and the model's facial scan underwent mandibular augmentation in the sagittal and vertical dimensions resulting in nine distinct facial profiles. Following these augmentations, the lips were adjusted anteriorly and posteriorly in 1.5 mm increments from baseline.
Results: Each of the nine facial profiles experienced significant within-group differences in preferred lip position. Females preferred more protrusive lips in all profiles than males. African Americans preferred more retrusive lips for nearly all profiles than Caucasians and Hispanics. Younger generations tolerated more retrusive lip positions compared with older generations for nearly all profiles.
Conclusions: Preferred lip positions are a function of convexity as opposed to divergence; facial types with vertical imbalances followed similar trends to those seen in other facial types with similar convexity. Sex, ethnicity, and age-related preferences persisted despite most facial imbalances
The Joppa Environmental Health Project: Evaluating Local Air Quality and Respiratory Health in Dallas' Environmental Justice Neighborhoods
No full textDue to historical racial segregation, People of Color (POC) and low socioeconomic status groups experience disproportionate exposure to particulate matter (PM) air pollution. Fine PM (PM2.5) pollution is associated with several health effects, including cardiovascular and lung disease, respiratory mortality, and adverse birth outcomes. There is a need to characterize environmental and health disparities in susceptible populations like environmental justice (EJ) communities. In Dallas, Texas, EJ communities such as Joppa and ���Singleton��� are POC neighborhoods that are surrounded by multiple pollutant sources. Using a community-based participatory research (CBPR) approach, the Joppa Environmental Health Project (JEHP) was formed in 2020 with the primary objective to assess residents��� perceptions of air pollution and other health concerns through a community household health survey and to evaluate PM pollution through the installation of a local air monitoring network. To carry out these objectives, the following aims are addressed in this dissertation: 1) apply a CBPR approach to facilitate community engagement and action-oriented research on PM pollution and respiratory health in Joppa; 2) quantify daily and monthly PM2.5 concentrations in Joppa and ���Singleton��� using low-cost sensors, PurpleAir and SharedAirDFW; and 3) examine the association between daily PM2.5 exposure and airway inflammation in children residing in Joppa.
Strong community engagement activities and efforts from our steering committee yielded a high neighborhood survey response rate (51%). A high lifetime asthma rate (18%) was also observed among survey respondents. Monitor data demonstrated elevated levels of PM2.5 concentrations in Joppa. Last, active airway inflammation was observed in children who were not diagnosed with asthma. Overall, the application of this research facilitated robust community engagement and resident-led research to address critical neighborhood concerns. Subsequently, an asphalt batch plant in Joppa voluntarily relocated operations in June of 2023. The steering committee organized a new group known as Justice for Joppa/Justicia para Joppa to sustain momentum created by this work, targeting local zoning and land use policies. Future work from this research will involve the placement of a permanent medical clinic in Joppa where residents will have access to long-term health support (i.e., chronic disease diagnosis and management)
The BAZ Family of Chromatin Remodelers in Colorectal Cancer: Insights into Oncogenesis, Alternative Splicing and Chemosensitization
No full textColorectal cancer (CRC) poses a significant healthcare challenge worldwide, necessitating a deeper understanding of the molecular mechanisms underlying its pathogenesis for improved therapeutic interventions. This thesis investigates the BAZ (Bromodomain Adjacent to Zinc finger) family of chromatin remodelers and their intricate involvement in CRC. The BAZ family members, including BAZ1A, BAZ1B, BAZ2A, and BAZ2B, exert critical regulatory functions in chromatin architecture and transcription, impacting various cellular processes from development to disease.
In colorectal cancer, BAZ1A is overexpressed, and its depletion resulted in diminished cell viability, increased apoptosis, augmented DNA damage, and cellular senescence, concomitant with the downregulation of components within the Wnt/��-catenin signaling pathway. In vivo studies corroborated these findings, revealing that knockdown of BAZ1A leads to diminished tumor growth and alterations in chromatin regulation. Interestingly, BAZ1A undergoes alternative splicing, which is promoted by treatment with histone deacetylase inhibitors, thereby highlighting its therapeutic potential. Remarkably, the full-length form of BAZ1A is implicated in DNA repair mechanisms, while its alternatively spliced counterpart is susceptible to increased DNA damage and sensitivity to DNA-damaging agents. These observations underscored the oncogenic role of BAZ1A in colorectal cancer and the importance of considering an oncogene���s alternative splicing patterns.
Similar to BAZ1A, BAZ2A is also upregulated in CRC and associated with reduced patient survival. Functional studies demonstrated their roles in inhibiting cell viability, colony formation, and modulating Wnt/��-catenin signaling. Inhibition of BAZ2A led to reduced tumor growth rates in mouse models, where it also affected histone modification patterns, favoring a less repressive chromatin state, and influencing major histocompatibility complex (MHC) regulation.
In contrast to BAZ1A and BAZ2A, BAZ1B knockdown enhanced cell viability, colony formation, and altered cell cycle progression, suggesting a tumor-suppressive role in metastatic CRC. BAZ1B impacted c-MYC expression independently of the Wnt/��-catenin pathway, and influenced p53 and p21 levels, implicating its involvement in tumor suppressive pathways.
Overall, the study underscores the potential of BAZ family members as therapeutic targets in CRC. Future research should focus on elucidating their molecular mechanisms, translating findings into clinical applications, and exploring combination therapies to improve treatment outcomes for CRC patients, thus advancing more personalized therapeutic approaches for CRC
Economic Indicators of the College Station - Bryan MSA, January 2025
No full textThe Business-Cycle Index decreased 0.2% from October 2024 to November 2024.1 The local unemployment rate increased to 3.3% in November 2024 compared to 3.2% in October. Local nonfarm employment increased by 0.04% from October 2024 to November 2024. Inflation-adjusted taxable sales decreased by 1% from October 2024 to November 2024. For 2023, the newly released Real Gross Domestic Product (GDP) for the College Station-Bryan MSA grew at an annualized rate of 3.9%, more than both the state of Texas (at 3.8%) and the entire U.S.(at 2.3%) over the same period
The BAZ Family of Chromatin Remodelers in Colorectal Cancer: Insights into Oncogenesis, Alternative Splicing and Chemosensitization
No full textColorectal cancer (CRC) poses a significant healthcare challenge worldwide, necessitating a deeper understanding of the molecular mechanisms underlying its pathogenesis for improved therapeutic interventions. This thesis investigates the BAZ (Bromodomain Adjacent to Zinc finger) family of chromatin remodelers and their intricate involvement in CRC. The BAZ family members, including BAZ1A, BAZ1B, BAZ2A, and BAZ2B, exert critical regulatory functions in chromatin architecture and transcription, impacting various cellular processes from development to disease.
In colorectal cancer, BAZ1A is overexpressed, and its depletion resulted in diminished cell viability, increased apoptosis, augmented DNA damage, and cellular senescence, concomitant with the downregulation of components within the Wnt/��-catenin signaling pathway. In vivo studies corroborated these findings, revealing that knockdown of BAZ1A leads to diminished tumor growth and alterations in chromatin regulation. Interestingly, BAZ1A undergoes alternative splicing, which is promoted by treatment with histone deacetylase inhibitors, thereby highlighting its therapeutic potential. Remarkably, the full-length form of BAZ1A is implicated in DNA repair mechanisms, while its alternatively spliced counterpart is susceptible to increased DNA damage and sensitivity to DNA-damaging agents. These observations underscored the oncogenic role of BAZ1A in colorectal cancer and the importance of considering an oncogene���s alternative splicing patterns.
Similar to BAZ1A, BAZ2A is also upregulated in CRC and associated with reduced patient survival. Functional studies demonstrated their roles in inhibiting cell viability, colony formation, and modulating Wnt/��-catenin signaling. Inhibition of BAZ2A led to reduced tumor growth rates in mouse models, where it also affected histone modification patterns, favoring a less repressive chromatin state, and influencing major histocompatibility complex (MHC) regulation.
In contrast to BAZ1A and BAZ2A, BAZ1B knockdown enhanced cell viability, colony formation, and altered cell cycle progression, suggesting a tumor-suppressive role in metastatic CRC. BAZ1B impacted c-MYC expression independently of the Wnt/��-catenin pathway, and influenced p53 and p21 levels, implicating its involvement in tumor suppressive pathways.
Overall, the study underscores the potential of BAZ family members as therapeutic targets in CRC. Future research should focus on elucidating their molecular mechanisms, translating findings into clinical applications, and exploring combination therapies to improve treatment outcomes for CRC patients, thus advancing more personalized therapeutic approaches for CRC
Amino Acid Type and Concentration Impact on Endothelial Nitric Oxide Synthase in Restructured Hams
No full textThis study investigated amino acid types, either singly or in combination, at varying concentration levels to determine which was most effective as a substrate for the endothelial nitric oxide synthase system (eNOS) enzyme to generate nitric oxide for its evaluation as an alternative curing system. Restructured hams were manufactured with pork semimembranosus muscle with a 20% brine consisting of salt, sugar, phosphate and sodium erythorbate and addition of either L-arginine (Arg), L-citrulline (Cit) or in combination (Arg/Cit) at concentrations of 1000, 3000 or 5000ppm. A nitrite (NaNO2) control (200 ppm) was also included. Hams were cooked to (71��C), chilled, vacuum packaged and analyzed on day 1, 7, 28 and 56 of refrigerated (4��C) storage for residual nitrate (RNO3) nitrite (RNO2) and nitroslyhemochromagen (NO-Heme). Sensory panel and textural attributes were analyzed on day 28. For RNO3 values an interaction (p=0.0001) was observed for amino acid type and concentration. Trends suggested 1000ppm concentration for amino acid treatment combinations resulted in higher NO3 values. The main effects of amin acid type and concentration did not affect RNO2 values in the restructured hams however all amino acid treatments produced ~2/3 of the amount of RNO2 than nitrite control. An amino acid type x concentration interaction (p=0.01) NO-Heme values. An amino acid x storage day interaction (p=0.001) NO-Heme values was observed, however, no amino acid treatment or concentration was more effective at generating NO-Heme values. Amino acid type influenced Cured Ham ID (p=0.004) and Ham Flavor Aftertaste (p=0.006) with Arg exhibiting scores closest in value to the nitrite control. Amino acid type also affected Soured Aromatic (p=0.03) and Chemical/Medicinal/Metallic (p=0.001) with Cit treated ham having the highest values for both attributes. An amino acid x concentration (p=0.0001) interaction was observed for objective Hardness values with Arg treated hams values increasing as concentration increased and exhibiting closest values to nitrite control. The data from this study suggests that Arg most effectively cures restructured hams by activation of the eNOS system to generate NO and that a concentration of 1000ppm may be sufficient
Essays in Monetary Policy and Household Expectations
No full textThis dissertation focuses on the formation and implications of household beliefs and expectations with respect to monetary policy.
In the first chapter, I investigate whether consumer sentiment (analogously referred to as confidence) matters for monetary policy. Specifically, I consider whether consumer sentiment responds to monetary policy shocks, as well as whether the responses of output, inflation, and unemployment depend on the state of consumer sentiment. Although various methods of measuring confidence/sentiment exist, the underlying goal of each is to gauge how the normative economic attitudes of households change over time. As such, asking whether consumer sentiment responds to monetary policy shocks can alternatively be viewed as whether monetary policy shocks change households��� perceptions of the current/future state of the economy. Additionally, while some of the variation in sentiment reflects movement in aggregate fundamentals, a number of papers have established that the unaccounted for portion has predictive power for a variety of macroeconomic variables. This observation motivates considering whether the state of consumer sentiment suggests different macroeconomic impacts of monetary policy shocks.
Using an external identification scheme in a local projections (LP) approach, I find that contractionary monetary policy shocks have only minor negative effects on consumer sentiment. Consumer sentiment is measured by the headline index published by the Michigan Survey of Consumers. Further, I find that this minor response persists across various states of inflation, business cycles, and interest rates. In contrast, I do find evidence that the state of consumer sentiment matters for how output, inflation, and unemployment respond to these shocks. Specifically, positive interest rate shocks during periods of depressed consumer sentiment have quicker and more contractionary effects on output and unemployment, while inflation is not responsive over short nor long term horizons.
In the second chapter, I utilize a novel feature of the Michigan Survey of Consumers (MSC) to identify whether respondent expectations change within tight windows around macroeconomic data releases. This feature of the data is the interview dates of respondents between June 1979 ��� May 2019. Over this period, I include releases of the Employment Situation Summary (ESS), Consumer Price Index (CPI), Industrial Production (IP), and Gross Domestic Product (GDP), as well as Federal Open Market Committee (FOMC) meetings and calls. Incorporating the interview dates of each respondent alleviates a major identification problem that has prevented previous empirical work from using the MSC data to address such a question. Without them, one would only know which survey the person was interviewed for, but not when it was conducted. Thus, it was not possible to discriminate between the different information sets of the respondents, thereby preventing identification of the change in inflation expectations in response to a particular release.
My work in this paper furthers our understanding of household inflation expectations along a number of dimensions. First, I find that expectations significantly respond to information about the unemployment rate and CPI inflation, indicating that these are more salient to households than the other releases. I measure the information being conveyed by the releases by using the size and sign of changes in the release relative to the previous periods value. Second, I consider whether the relevance of these releases differs during recessions, the first paper to empirically address such a question. I find that information about the unemployment rate is particularly salient preceding, during, and following recessions. The final contribution I make in this paper is the finding that, over a shorter subsample, unanticipated changes in output growth prompt households to adjust their inflation expectations. Here, unanticipated refers to the difference between the realized value and Bloomberg consensus forecast value for each release, wherein inflation expectations respond to such deviations in IP and real GDP growth
Higher-Dimensional Data in Powder-Bed Fusion Additive Manufacturing: A Path to Improved Printability Predictions
No full textThis dissertation explores the optimization of alloy design and process parameters in metal additive manufacturing (AM), specifically focusing on powder bed fusion (PBF) processes like laser powder bed fusion (L-PBF) and electron beam powder bed fusion (EB-PBF). Conventionally, process parameters for well-known alloys were optimized in hopes of achieving properties similar to those obtained using traditional manufacturing methods. However, the potential of AM processes, particularly PBF, demands the development of alloys tailored to exploit these unique benefits. The complexity of PBF systems, with numerous design degrees of freedom, necessitates a strategic approach to alloy design and process parameter optimization.
To address these challenges, this dissertation introduces two frameworks centered around the use of higher-dimensional data. The first framework is a purely data-driven model that efficiently explores composition and process parameter spaces. Drawing from a database collected from the literature and in-house experiments, this screening tool incorporates classification techniques to predict process defects and identify regions conducive to good printability. Alloys with larger printability regions are better suited to be fabricated using PBF processes.
The second framework is a physics-based model for the fine-tuning of metal alloy printability. Overcoming challenges present in current frameworks, this model employs dimensionality reduction techniques and regression methods to predict higher-dimensional spatial thermal field outputs instead of relying on lower-dimensional melt-pool dimensions. This approach allows for predicting melt-pool dimensions at varying layer thicknesses and beam spot sizes without the need for additional experiments. This allows for the exhaustive exploration of the process parameter design space.
Overall, the dissertation���s focus on leveraging higher-dimensional data provides a comprehensive and efficient methodology for advancing alloy design and optimizing process parameters in PBF processes, contributing to the evolution of metal additive manufacturing
System-Level Rotordynamic Analysis of Centrifugal Compressors Using Computational Fluid Dynamics (CFD), Design and Optimization of Novel Swirl Brakes
No full textThe accurate characterization of compressor rotordynamic coefficients during the design phase reduces the risk of subsynchronous vibration (SSV) problems occurring in the field. Although rotordynamists extensively investigate discrete compressor components (such as seals and front shrouds) to tackle instability issues, integrated or system-level analysis of compressor rotordynamics is very scarce. In reality, the impeller, eye labyrinth seal, and the front shroud heavily influence one another; and the collective dynamic behavior of the system differs from the sum of the dynamic behavior of isolated components. Furthermore, American Petroleum Institute (API) level II vibration stability analysis requires inclusion of all possible destabilizing forces including those that stem from seals and the front shroud cavity.
A CFD-based approach is taken to evaluate the dynamic behavior of the system as a whole. The geometry and operating conditions in this work are based on a recently published experimental study on centrifugal compressor. The commercial CFD code CFX 19.0 is used to resolve Reynolds Averaged Navier-Stokes (RANS) equations to quantify the eye labyrinth seal and front cavity stiffness, damping, and added mass. The entire compressor stage is modeled to uncover the coupled behavior of the components and assess the stability of the whole system instead of just discrete components. In the current work, three CFD approaches, namely quasi-steady, transient static eccentricity, and transient mesh deformation techniques are studied and benchmarked against analytical and experimental results from the literature. Having established the efficacy of the proposed approach, 4 types of swirl brakes are proposed and analyzed for stability. The novel swirl brakes create negative swirls at the brake cavities and stabilize both the front shroud and the eye-labyrinth seal simultaneously. The designed swirl brakes are further investigated to identify contribution of each geometric feature of the brakes to the rotordynamic stability of the whole system/stage. The geometric parameters chosen for the parametric study are the height of the slot cavity, the number of slots, the length of slots, the slot angle and the direction of slot curvature