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Chronic IL-1 Exposure Drives Prostate Cancer Progression
No full textProstate cancer (PCa) is the second most common cause of cancer-related deaths
among American men. Androgen Receptor (AR) transcriptional activity is required for
PCa tumor growth. Androgens regulate normal prostate tissue growth and differentiation
via androgen receptor (AR) activation. Due to the role of androgens in prostate cancer,
androgen-deprivation therapy (ADT), either through chemical or surgical castration or
the use of anti-androgens, has become the standard therapy. However, ~10-20% of
PCa patients will develop treatment resistance, referred to as castration-resistant
PCa (CRPC). One mechanism of CRPC is the loss of dependence on AR for cell growth
and survival. As such, over 84% of CRPC patients will develop incurable, lethal
bone metastasis. Thus, it is important to uncover the mechanisms that drive CPRC.
IL-1 is elevated in PCa patient tissue and serum and is associated with disease
progression and metastasis. IL-1 is clinically relevant, but the role of IL-1 in CRPC
development is not fully elucidated. Chronic inflammation is a known hallmark of cancer
initiation and progression. Therefore, we exposed the cancer cells to IL-1 for several
months to make the chronic IL-1 sublines, LNas1 and LNbs1. The chronic IL-1
sublines restore AR and AR activity but evolve AR independence and acquire a
constitutive p62-KEAP1 interaction. p62 is a multi-domain, multifunctional pro-survival
protein that mediates autophagic turnover of damaged proteins and organelles,
promotes NF-κB inflammatory signaling and induces NRF2 antioxidant signaling
through its binding to and sequestering of KEAP1 from NRF2. Despite constitutive p62-
KEAP1 binding, the chronic IL-1 sublines only show elevated NRF2 signaling in the
NRF2 target genes, HMOX1 and GCLC. Furthermore, the chronic IL-1 sublines evolve
insensitivity to IL-1 extracellular signaling and, thus, do not activate NF-κB nor NRF2
signaling. Thus, the regulation and function of the constitutive p62-KEAP1 interaction in
the chronic IL-1 sublines is novel. To investigate the regulation and function of the
constitutive p62-KEAP1 interaction in PCa cells chronically exposed to IL-1, I dissected
p62-KEAP1 regulation and function under the oxidative stress-inducing stimulus,
androgen deprivation. Under androgen deplete conditions, there is attenuation of
HMOX1 and overexpression of GCLC in the chronic IL-1 sublines. This suggests that
there is active but aberrant NRF2 signaling that may allow these cells to be primed to
withstand oxidative stress. Furthermore, knockdown of KEAP1 results in upregulation of
HMOX1 suggesting that KEAP1 negatively regulates HMOX1. Both HMOX1 and GCLC
function as an antioxidant to attenuate iron-induced lipid ROS and thus regulate iron-
dependent cell death known as ferroptosis. Based on what we have found, we
hypothesize that the sublines activate a novel pathway that primes them to withstand
ferroptosis-induced cell death
Papers on Disruptions in Property Rights and Performance in Residential Real Estate Assets and Non-profit Organizations
No full textTheories in law, finance, and economics make a variety of predictions linking property rights to
more complete capital markets, improved firm performance, reduced risk, improved worker
outcomes, and higher asset prices. Reliably testing these predictions is critical, and properly
identified models can help resolve the disputes among these theoretical literatures. I use three
empirical settings to identify the effects of reduced property protections: when state government
lowers protections for residential real estate owners by making squatting on property easier,
when state government forbids evictions during the COVID-19 pandemic, and when criminal
actors deprive unsuspecting non-profits of significant amounts of property. In all three instances,
theories in economics and finance differ on the potential outcomes for stakeholders. My research
shows that the impact is decidedly negative for residential real estate owners, landlords, and nonprofits when they experience tampering with their respective property rights
Millimeter-wave Packaging Materials and CPW Interconnects on Silicon
No full textAccurate millimeter wave (mm-wave) circuit and system design is challenging due to un-
known dielectric properties above 40 GHz, higher loss due to multimode propagation in
substrates, and electromagnetic modeling limitations when compared with on-wafer mea-
surement. This dissertation attempts to address these challenges by studying material char-
acterization techniques and coplanar waveguide (CPW) line performance on silicon wafers.
The dielectric characterization techniques have been investigated from 10 MHz to 110 GHz
for substrates and fixed thickness packaging dielectrics. Broadband data using a coaxial line
technique was demonstrated for the first time in literature up to 67 GHz. The accuracy of the
properties improves for material thicknesses which are greater than half wavelength. For the
thin samples, a stacking technique has been introduced to electrically increase the thickness.
The broadband data was achieved using a single 1.85 mm airline from 10 MHz to 67 GHz,
followed by a WR10 waveguide from 75 to 110 GHz. As resonant techniques are more accu-
rate, a microstrip ring resonator was used where the copper trace was printed using a craft
cutter tool and was adhered onto non-copper clad materials. This is a fast, low-cost, and
non-destructive solution and is suitable for frequencies below 20 GHz. This study will en-
able high frequency design solutions for packaging technologies used for antennas-in-package
(AiP) and three dimensional (3D) printed RF circuits. Next, broadband loss characterization of coplanar waveguide (CPW) transmission lines has been studied on undoped high
resistivity silicon (HRS) from 10 MHz to 325 GHz. Electromagnetic (EM) modeling limi-
tations in the Ansys HFSS simulation tool have been examined for full thickness wafers of
525μm and two innovative EM ports were introduced. The bridge-probe lumped port model
showed promising results to address the probe parasitics at high frequency. The tunnel wave-
port showed simulation capability up to 325 GHz which otherwise would be limited to 80
GHz using general waveport for 400 μm thick substrates. The on-wafer measurement data
shows that unwrapped ground, narrow ground width and thinning of substrates can reduce
the loss of the lines. A glass spacer was used to separate the wafer from the probe station
chuck. Compared to simulation, higher loss was observed in the measured data up to 110
GHz due to a possible unavoidable parasitic surface channel in silicon. This problem can be
mitigated by surface passivating the silicon. At frequencies from 140 to 325 GHz, this issue
was not observed. The loss of the conventional CPW lines has been used as a baseline to
characterize the performance of copper nanowire interconnect technology integrated within
the lines. This work can contribute to the advancement of copper-to-copper interconnects
for die-to-wafer or wafer-to-wafer connections for 3D packaging technology. The potential of
HRS for passive device design was further explored by introducing short and open stubs on
the center conductor of CPW lines as filter elements operating up to 325 GHz which showed
excellent response compared with simulation
Synthesis of Functionalized Polycaprolactones for Drug Delivery Applications
No full textPolycaprolactones (PCLs) have been used in various applications due to their biodegradability,
biocompatibility, and favorable mechanical properties. The ability to attach multiple
functionalities in the PCL backbone can provide many possibilities to tune the polymer’s
physicochemical properties. Among the applications, extensive efforts have been dedicated to
developing PCLs as carriers of bioactive compounds; however, some limitations still encountered
are low payload, instability, and uncontrolled release of the cargo. In this work, micellar drug
delivery systems obtained from the self-assembly of amphiphilic block copolymers comprising of
benzyloxy- and oligo(ethylene glycol)-substituted PCLs were designed to load the doxorubicin
anticancer drug and a quercetin cardioprotective polyphenol. The co-loading approach provided a
way to enhance the loading capacity of the micelle for both cargoes. The utilization of various
lengths of oligo(ethylene glycol) side-chains permitted tuning of the polymer’s thermoresponsive
behavior to modulate the release of the cargo. These micelles exhibited a low critical micelle
concentration, which is necessary for tolerating severe dilutions. Many copolymers have been
explored for drug delivery; however, amphiphilic homopolymers can also be an alternative due to
their more straightforward synthesis. Most reported amphiphilic homopolymers have a nonbiodegradable backbone, exhibits pH-dependent assembly, and are charged. Herein, non-ionic
amphiphilic PCL homopolymers readily self-assembled to form micelles. The potential of using
these micelles as drug carriers were explored by loading a eugenol anti-inflammatory molecule
The Effects of First Impressions on Predicting Honesty Outcomes Using Audiovisual Integration
No full textPeople automatically and unconsciously process first impressions of faces and voices
during social interactions. There are consequences to our first impressions because they can
influence and predict a variety of societal outcomes including dating choices, voting behaviors,
job interview success, and judicial court rulings. The implications of first impressions also affect
perceptions of honesty. As a result, the first impressions we form influence how we evaluate
honesty. Perceptions of honesty involve evaluations of how honest, truthful, or deceptive
someone appears in a situation. In first impression research, perceptions of honesty (i.e., honesty
evaluations) usually focus on high-stakes honesty judgments (e.g., judicial case rulings, police
lineups, and police investigations). However, the effects of first impressions on perceptions of
honesty are present in our daily social interactions and affect mundane aspects of our lives. For
example, in our daily social interactions, we form first impressions of individuals, and this
affects how we perceive the honesty of these individuals’ opinions, preferences, excuses, or ideas
(i.e., low-stakes honesty evaluations). The first goal of this project was to examine whether
instantaneous first impression judgments of trustworthiness and dominance predict honesty
outcomes in a low-stakes situation. The results suggest that initial perception of trustworthiness
predicts honesty evaluations but only during shorter durations of honesty evaluations. Thus, if
participants are presented with longer durations to evaluate honesty, initial trustworthiness
ratings do not predict honesty outcomes. The second goal was to examine the early stages of first
impression trait judgments and honesty evaluations using thin slices (i.e., 8 and 15-second clip
excerpts from video and audio). A minimum of 8 seconds was chosen to give participants
enough time for top-down processing and in return, they will have enough information to be able
to evaluate honesty. A maximum of 15 seconds was chosen to give participants extra time to
process stimuli but not too much time so that there is less risk of attention loss.
The results suggest that when participants are given more time to evaluate honesty and
trustworthiness the judgments are more positive, which supports the truth-bias theory. The third
goal was to examine whether face and voice cues significantly influence perceptions of
trustworthiness (video) and dominance (audio), respectively. Results were consistent with earlier
findings that suggest voices are linked to dominance. Videos of individuals describing a movie
they liked or disliked that are consistent or inconsistent with their true opinion were used
The Offering Plate is Off the Table: the Impact of COVID-19 on Church Fundraising
No full textIn the spring of 2020, the global COVID-19 pandemic caused many churches in the United
States to cease in-person services for an unknown period of time. Unfortunately, numerous
methods of appeal used by churches relied upon in-person parishioner engagement that was no
longer an option. This study used an online survey of churches in Dallas County and interviews
of church leaders to examine the impact of COVID-19 on church fundraising. The results of this
study indicate that prior to COVID-19, churches primarily relied upon in-person requests made
during a sermon or at a church activity. During COVID-19, churches increased their use of social
media to keep parishioners engaged and to ensure that parishioners maintained an awareness of
the funding needs of the church. Churches also increased their use of other online
communication resources, such as websites, YouTube and email, to meet the spiritual needs of
parishioners whose motivation to give is based upon their religious beliefs and commitment to
the church
Can National-level Institutions Impact Democratic Transitions? Some Evidence From the Arab Spring
No full textIn the aftermath of the historic Arab Spring wave of pro-democracy revolutions that engulfed the
Middle East from 2010-2011, Tunisia emerged as the sole success story, achieving a stable
multi-party constitutional system. Egypt meanwhile slid back into its old status quo of military
domination over the political system after the 2013 coup against elected president Mohamed
Morsi. In each case, three major national-level institutions—the military, religious parties, and
labor unions—played a significant role in the success or failure of each country’s post-
revolutionary transitional process. This dissertation explores what gaps exist in our present
knowledge about the potential of these three institutions to cause democratic revolutions and
transitions to succeed or fail through the experiences of Tunisia and Egypt. After providing a
brief history of the changing politico-economic circumstances in the Arab world that led to the
demonstrations of 2010-2011, the dissertation moves on to compile and compare existing
academic theories about potential behavior of the military, religious parties, and labor unions
during and after pro-democracy uprisings. It then outlines the case studies of Tunisia and Egypt,
documenting the historical evolution and behavior of all three institutions during and after each
country’s revolution. After this, it analyzes how well existing academic theories explained the
behavior of each institution in Egypt and Tunisia and uses this to identify holes in our present
knowledge. Finally, this dissertation concludes by proposing a new theory of military behavior in
post-revolutionary transition periods, an area largely unexplored by current research, as well as
proposing a new theory of what factors position labor unions to steer a democratic transition
process. Along with this, it argues that its exploratory model framework can readily be adapted
to other country and institution case studies outside the Arab world
Characterizing the Role of Heme in Alzheimer’s Disease Pathogenesis
No full textIn humans, heme accounts for 97% of functional iron. With a porphyrin ring and an iron ion, heme
possesses structural and chemical features fitting for electron transfer, oxidation/reduction, and
interaction with oxygen. Three oxidative phosphorylation (OXPHOS) complexes, II, III, and IV,
require heme for proper functioning. Cells that require high levels of adenosine triphosphate
(ATP) and OXPHOS require elevated levels of heme. Heme also serves as a powerful antioxidant
for cells because it can be degraded to biliverdin and reduced to bilirubin. The reduction of
biliverdin to bilirubin helps relieve reactive oxygen species (ROS) in cells.
Neuronal cells are known to be high-energy demanding cells that depend on mitochondrial
respiration to function. Specifically, in neurodegenerative diseases such as Alzheimer’s Disease
(AD), mitochondrial dysfunction is one of the key characteristics associated with the progression
of this disease. Oxidative stress has also been implicated in the pathogenesis of AD. Due to the
role of heme in both of these cellular functions, it is important to understand how heme
contributes to neuronal function and how it may play a pivotal role in developing this
neurodegenerative disease.
The objective of this research is to dissect the role of heme in the pathogenesis of AD. Utilizing
immunocytochemistry and Western blot techniques, I have depicted the importance of heme in
neuronal development. Heme uptake, synthesis, and degradation are significantly increased in
developing and differentiating neurons. This increase in heme flux coincides with an increase in mitochondrial proteins. Using the APPPS1 mouse model and microarray expression data of
human patients, I detected specific heme-related enzymes that are downregulated in AD. These
alterations can lead to a decrease in the availability of heme for cellular functions. The decrease
in heme availability can lead to disturbed mitochondrial function and an increase in oxidative
stress.
Furthermore, to glean whether heme flux alterations are early and potentially initiating causes
of AD, I utilized patient-derived neurons generated from human-induced pluripotent stem cells
(iPSCs). These studies revealed a distinct role of heme in the development of familial (FAD) and
sporadic AD (SAD). SAD neurons have downregulated heme synthetic and degradation enzymes,
while FAD neurons only had a slight yet significant reduction in the biliverdin reductase B (BLVRB)
enzyme involved in heme degradation. Moreover, analysis of the tricarboxylic acid (TCA) cycle
enzymes and intermediates revealed a significant alteration in enzymes and intermediates within
both SAD and FAD neurons relative to gender-matched controls. This study revealed that
although heme flux alterations are likely an early event in SAD pathogenesis, perturbations in the
TCA cycle are probably a common characteristic of both SAD and FAD
Time-varying Sources and Vascular Contributions to Age-accompanied Functional Brain Network Re-organization
No full textThe brain is a complex network of interacting brain areas that can be further divided into
segregated functional systems. Resting-state system segregation is a feature of brain network
organization that has relevance to brain function in both health and disease across adult lifespan.
It is unclear what gives rise to system segregation and the individual differences in this brain
network measure. In this dissertation, two aspects of this important question are investigated: (1)
Do vascular factors contribute to relationships between age and system segregation across the
adult lifespan? and (2) Can sources of time-varying information help account for relationships
between aging and system segregation? The interplay between these questions reveals how the
temporal evolution of system re-configuration at a short time scale impacts more stable
individual features of large-scale network organization, in the context of differences in vascular
health of adult individuals. This dissertation was accomplished by incorporating data from a total
of 894 unique participants, over 3 independent studies (age range: 20 – 100 years) and including
multiple neuroimaging modalities and measures of participant health and demographics.
The contribution of vascular factors towards relationships between age and resting-state system
segregation is first investigated. There exist relationships between age and vascular measures,
including cardiovascular health (CVH) and cerebrovascular reactivity (CVR). Age-related
decreases of system segregation persist after controlling for vascular-related variance. This is
demonstrated by (i) computing system segregation regional CVR-corrected signals within each
participant, and (ii) including CVH as a participant-level covariate in the models. These results
demonstrate that age-related differences in system segregation cannot be fully attributed to
differences in cerebrovascular and cardiovascular factors.
To examine the contribution of time-varying information to system segregation, I examine the
relationship between resting-state BOLD signal variability and system segregation. After
controlling for vascular confounds by (i) estimating BOLD variability using CVR-corrected
signals, (ii) including CVH as a covariate in the model, there is an absence of a relationship
between age and BOLD variability, revealing that vascular factors serve as a major source of
variance explaining previously reported relationships between age and resting-state BOLD signal
variability. Further, with correction of vascular factors, BOLD variability does not relate to
system segregation.
An additional source of time-varying information is evaluated in relation to system segregation,
focused on co-fluctuation amplitude of the resting-state time-series. Moments of greater co-
fluctuation pattern across edges are identified (events), during which functional brain networks
are highly modular relative to non-event moments. I demonstrate that the number of events that
are present in an individual’s resting-state time-series is related to their system segregation.
However, I next demonstrate that age-accompanied decreases of system segregation are evident
across all the moments, irrespective of co-fluctuation amplitude of edges. Collectively, these
findings reveal that while high co-fluctuation moments (events) may contribute towards
establishing an individual’s system segregation, brain network re-organization exists across all
time points of a resting-state scan.
In sum, this dissertation provides important support that resting-state system segregation
measures brain network re-organization across the adult lifespan. This measure is independent
from vascular differences within individuals, and provides critical evidence of brain aging that is
consistently evident across periods of rest. Serving as a biomarker of functional brain network
integrity, system segregation further supports the application of this approach towards measuring
individual brain health across the lifespan
Cultural Modulation of Moral Regulation: Prescriptive vs. Proscriptive Morality
No full textMorality is an integral part of our life to foster social integration and group living. To behave
morally, individuals must be attentive to two types of moral regulation—(a) prescriptive morality
(“what people should do”) and (b) proscriptive morality (“what people should not do”). Although
both modes of moral regulation are widely recognized and endorsed across different cultures,
which form of morality is given more emphasis may vary by cultural contexts. In this
dissertation research, I conducted three studies to address three aims: (1) to test cultural variation
in the relative significance of prescriptive vs. proscriptive morality, (2) to examine the
underlying motivational (approach vs. avoidance motivation) and emotional (guilt vs. shame
proneness) mechanisms for the cultural variation, and (3) to examine what implications this
cultural difference may have on reactions to moral violations. In Chapter 1, theoretical
backgrounds for the current research are discussed. Chapters 2-4 discuss findings from Studies 1-
3 based on the comparisons between European Americans and East Asians. Three key findings
emerged. First, across three studies, European Americans ascribed more moral weight to
prescriptive morality than did East Asians, while there was no cultural difference in proscriptive
morality (Aim 1). Second, Studies 1 and 2 showed that the cultural difference in prescriptive
morality was mediated by European Americans’ higher levels of guilt proneness compared to
East Asians, thereby elucidating the emotional mechanism for the cultural variation. In contrast,
there was no evidence that approach vs. avoidance motivation accounted for the cultural
difference in prescriptive morality (Aim 2). Third, Studies 2 and 3 tested whether culture
moderates the extent to which people are critical of targets who committed violations of
prescriptive or proscriptive morality using a newly developed task of moral violation (Aim 3).
Unexpectedly, the two cultural groups did not differ both in their self-reported (Study 2) and
behavioral (Study 3) reactions to either type of moral violation. Finally, theoretical implications
of these findings are discussed in Chapter 5