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Examining the Efficacy of Neural Stimulation for Reducing Paranoid Ideation and Improving Social Functioning in Schizophrenia
No full textInnovative treatments for paranoia are urgently needed in Schizophrenia Spectrum Disorders
(SSD) as this symptom is closely linked to the poor social relationships and impaired community
functioning seen in this vulnerable population. As such, this project aimed to assess whether
transcranial direct current stimulation (tDCS) to ventrolateral prefrontal cortex (VLPFC) can
attenuate paranoia and enhance social functioning in SSD.
A double-blind, within-subjects, crossover design was used to compare the effects of active vs.
sham tDCS in 50 participants with SSD and current/recent paranoia. In addition to laboratory
measurements, Ecological Momentary Assessment (EMA) was utilized to quantify real-world
effects of stimulation in daily social interactions. Each participant completed three visits (i.e., 1
enrollment visit and 2 stimulation visits) and three EMA periods in total.
Results showed that tDCS significantly reduced state paranoia, in that participants showed
greater reductions in state paranoia after receiving the active stimulation compared to the sham
procedure. Active stimulation also contributed to improvements in paranoia-related outcomes
measured in the lab, including reduced self-reported hostility, decreased attributions of blame
and hostility in ambiguous situations, and increased trustworthiness ratings of strangers’ faces.
However, brain stimulation did not change participants’ self-reported recent social functioning.
Regarding potential improvements in daily life as measured by EMA, participants’ daily
paranoid thinking did not differ significantly between EMA periods (baseline vs. active vs.
sham). However, we found that participants reported higher motivation to interact with others in
the EMA-active period compared to their baseline and the EMA-sham period. Participants also
perceived others as being more trustworthy and warm in daily social situations in the EMA-
active period compared to their baseline.
The current project provides initial evidence that applying tDCS to the VLPFC is effective in
reducing paranoia and improving social functioning in patients with SSD, as further discussed in
Chapter 8
Engineered Proteinaceous Materials and, Their Applications in Vaccine Development
No full textRecent advancements in immunotherapy and vaccinology have exploited recombinant proteins
and inactivated whole organisms to replace live-attenuated pathogens, which are typically used as
immunogenic agents. Structural stability of these plays a pivotal role in efficient antigen
presentation to major histocompatibility complexes (MHC). Processing of antigenic peptides by
MHC is an important factor in stimulation of strong immune responses. Unfortunately, most
proteinaceous materials and inactivated whole organisms undergo significant structural changes
during vaccine development, leading to poor antigen presentation, and eliciting low
immunogenicity in vivo. Despite years of effort to improve stability of proteinaceous materials,
only a few of approaches exist, and development of methods to increase their structural stability
and guarantee their proper antigen presentation in vivo are still needed. In this work, we
demonstrate that coordination polymers formed through the interlinking of organic ligands and
metal centers, can help overcome the structural stability issues related to proteinaceous materials.
Our methods not only provide structural stability in vitro but have also shown immunogenicity
improvement when tested in vivo.
The first chapter reviews the concept of supramolecular self-assembly, process by which materials
with different physiochemical properties can be obtained. Virus-like particles are then introduced,
and several different applications of these briefly discussed.
The second chapter describes an innovative method for construction of near-infrared particles used
for non-invasive imaging in vivo. The resulting composites show great promise as candidates for
in vitro cellular and deep tissue imaging in vivo.
The third chapter elaborates on the stabilization of liposomes, transmembrane proteins, and
proteoliposomes through their encapsulation in zeolitic-imidazolate frameworks. The resulting
composites show enhanced stability against harsh conditions (e.g., high temperatures, mechanical
stress, and denaturing agents).
The fourth chapter reviews commonly used polymer-based materials for vaccine development.
Further, it elaborates on the rationale behind the utilization of such materials and discusses some
of the current obstacles faced by in the vaccine manufacturing field. It concludes with a perspective
on technologies that could help the field overcome such obstacles.
The fifth chapter introduces the fabrication of whole-cell vaccines against bacterial infections
using metal-organic frameworks. It systematically presents details about the synthesis, in vitro
assessment, and in vivo testing of the vaccine against uropathogenic E. coli.
The sixth chapter shows the generalizability of metal-organic frameworks to produce whole
vaccines using different types of bacterial strains. It presents the importance of different T-cells
for proper development of immunity against recurrent urinary tract infections and how ZIF-8 based
vaccines can successfully recruit such cells
Molecular Dynamics Investigation of Fluoride Ion Permeation and Mechanism in Fluoride Export Protein Bordetella Pertussis (Bpe)
No full textMicroorganisms struggle to survive numerous chemical threats, one of which is fluoride ions to
which they developed fluoride channels (Fluc) for exporting fluoride out of their cytoplasm. The
crystallographic structure and previous studies have spotted an unusual tetrahedrally coordinated
non-transported central sodium cation and highlighted certain conserved polar residues along the
Fluc pores. However, the exact coordination number of the central sodium and the mechanism of
fluoride permeation in relation to these conserved polar residues remains elusive. In this study, we
applied the all-atoms molecular dynamics method on WT Fluc-Bpe (Bordetella pertussis) with
single fluoride in its pore and with four fluorides alongside its arginine mutants (R23A and R23K).
We investigated the possible hydration of central sodium ion to ascertain its coordination, the role
of arginine 23, which is an important conserved polar residue, and the permeation mechanism of
fluoride. We found out using the watershell analysis that sodium was anhydrous in the WT Fluc
and its mutants but hydrated to form a 5-ligand coordination in WT Fluc systems with single
fluoride in Fo and F2 binding sites. The dihedral analysis of arginine 23 revealed that it plays a
pivotal role in the stabilization of fluoride ions by electrostatic non-bonded interactions made
possible by its guanidinium side chain which undergoes dihedral shift for fluoride permeation and
efflux. The mechanism of fluoride export for each protein system under study provides insight into
the structural dynamics of Fluc’s important arginine polar residue
Accountability Overload and Its Consequence and Remedy
No full textAccountability overload (AO) may increase cost, lower responsiveness, and decrease productivity and service quality [103]. It creates an extra burden on employees [163], erodes their
trust and morale [185], and decreases their job satisfaction [43]. Specifically, it undermines
organizational mission [15, 68] and performance [140, 152, 155]. However, the examination
of the phenomenon and its consequence and remedies is still in a nascent stage and predominantly qualitative. This dissertation undertakes three interrelated studies to fill the
research gap by advancing the concept, empirically examining the relationship between AO
and organizational outcome, and exploring remedies to AO.
The first study conducts a systematic review of Public Administration literature on AO.
The second study empirically examines the relationship between AO and the performance
of public servants across societal cultures. The third study investigates the effect of ethical
leadership (EL) on AO and the mediating role of the ethical environment (EE) on the
relationship between EL and AO.
The first study identifies the elements of AO and its consequence and remedy. The most
common element of AO is multiple accountabilities or expectations. Besides, incompatibility
between accountability criteria and organizational goals, ambiguous performance standards,
and excessively high accountability or performance requirements are some of the dominant
elements of AO. In addition, episodic and arbitrary accountability demand, incomplete outcome measures, emphasis on punitive actions, and lack of legitimacy of the accountholder
are the factors that contribute to AO.
The study suggests that AO generally produces negative consequences: it undermines performance and organizational objectives and makes the accountability system ineffective. Collaboration and dialogue, moderate accountability requirements, appropriate performance
criteria, ethical practice in the organization, and an emphasis on the organizational mission
may reduce AO. Contextual factors such as poor governance and lack of trust in government
influence AO in the organization. However, extant studies are predominantly qualitative and
concentrated in a limited number of countries. Thus, the study emphasizes empirical investigation into AO in comparative settings to appreciate the phenomenon and its consequences
and remedies.
The second study defines perceived AO and finds a negative association between AO and
employee performance. It also proves that the relationship between performance and AO
does not vary across societal cultures. Therefore, the study concludes that AO is a universal
phenomenon and has a similar consequence irrespective of differences in contexts or cultures.
The third study finds that EL reduces AO among employees and enhances EE in the organization. However, EE does not influence the relationship between EL and AO. Thus, the
study underscores the importance of EL in reducing AO among employees irrespective of
the ethical condition in the organization
Towards a High-performance and Reliable System for Emerging Edge Network
No full text5G is a new paradigm that enables tremendous opportunities by delivering high-bandwidth
and low-latency network. The emerging 5G-enhanced applications including smart home,
smart factory, Artificial Intelligence (AI), Augmented Reality (AR)/ Virtual Reality (VR)
and autonomous driving are widespread through the deployment of the 5G. In responding
to the fast-varying user service requirements and highly mixed traffics, Network Function
Virtualization (NFV) technique is emphasized by the 5G to enhance its functional and architectural viability. NFV is a novel paradigm that packages the network services as virtual
machines (VMs) or containers on Commercial-Off-The-Shelf (COTS) servers instead of traditional vendor proprietary hardware devices. In this dissertation, we focus our performance
characterization and optimization on the emerging virtual Radio Access Network (vRAN)
system enabled by the NFV technique, since it plays a vital role in today’s edge infrastructure
for its better support for the latency-sensitive applications.
The vRAN has become an essential infrastructure to deploy the emerging edge applications,
especially in the new-coming Infrastructure-Augmented Autonomous Driving (IAAD) system. This dissertation sets to illustrate the key challenges and their corresponding solutions
of the vRAN’s infrastructure/architecture, mainly focusing on the vRAN’s Single Instruction
Multiple Data (SIMD) mechanism and its management/control layer, to match the deployment requirements of the emerging edge applications from the performance and reliability
perspective.
To guarantee the performance and the reliability of the emerging edge applications, the
vRAN edge network infrastructure must possess the ultra-low latency feature which is
scarcely achievable by the traditional network infrastructure. However, the vRAN edge
network infrastructure, specifically the Commercial-Off-The-Shelf (COTS) servers, has limited computing resources, which will hinder the vRAN edge network to meet the latency
requirement applied by the emerging edge applications. Moreover, the vRAN edge applications have fundamentally differentiated computing algorithms which will ignite various
resource utilization patterns. Consequently, there exists ”Inefficient computing resource utilization” caused by the mismatch between emerging edge applications’ properties and the
COTS micro-architectural structure, which will degrade the performance of the edge applications. Besides, the emerging edge applications, especially the IAAD system, demand
ultra-high reliability provision for the vRAN edge system. However, the current vRAN can
not satisfy the provisions requested by the new-coming IAAD system, which will expose the
IAAD system to the severe safety issue.
To tackle the challenges, we propose a SIMD consciousness computing mechanism and a data
fusion awareness management methodology to thoroughly exploit the micro-architecture of
the state-of-the-art COTS servers and entirely utilize the management layer of the current
vRAN infrastructure. The proposed solutions can effectively promote the vRAN infrastructure’s performance and the reliability of the emerging IAAD system. Specifically, 1) We
implement a thorough architectural characterization on the key network components and
MEC applications on the vRAN edge system to provide guidance on the hardware architecture design trade-off of vRAN edge COTS servers. 2) We propose ”Arithmetic Ports
Consciousness Mechanism” (APCM) to exploit the idle architecture resources to eliminate
the ubiquitous backend bound of the current vRAN infrastructure and promote the throttled
bandwidth between the COTS server’s registers and L1 cache. 3) We develop a new architecture between the COTS server’s registers and L1 cache to avoid the congestion caused by the
data arrangement procedure of the vRAN system and the emanating AI applications, which
will effectively accelerate the proceeding of the current edge infrastructure.4) We create a
Spatial-Temporal (S-T) fusion layer above the current control layer to tackle the edge network fluctuation challenges of the current vRAN infrastructure to guarantee the reliability
requirement applied by the emerging IAAD system.
This dissertation aims at developing a high-performance and reliable system for the emerging
edge network to deploy emerging AI-enable applications and IAAD system efficiently and
effectivel
Contributions of Specific Peripheral Nociceptor Signaling Pathways to Analgesia
No full textChronic pain represents a massive socioeconomic burden, impacting the lives of 1 in 5
Americans. Existing therapeutics vary widely in both efficacy and availability. Understanding
the mechanisms behind chronic pain, including any sexually dimorphic differences, drives the
search for novel, efficacious therapeutics. Interestingly, pain correlates with metabolic stress in
peripheral sensory neurons; alleviating this metabolic stress relieves chronic pain conditions. We
have thus sought to investigate neuronal metabolism in chronic pain in two ways. Our first study
involves disrupting the ability to appropriately respond to metabolic stress by deleting liver
kinase B1 (LKB1) from peripheral nociceptive neurons marked by Nav1.8 and exposing animals
to a stressor in the form of a 24-hour fast. Whereas females experienced LKB1-mediated
hypersensitivity, males experienced an initial genotype-independent period of mechanical
hypersensitivity, which was maintained in an LKB1-specific fashion. In females, LKB1 was
requisite to generate sufficient mitochondrial activity to counteract the fast; male mitochondria
were unaffected by fasting. Interestingly, in a model of paclitaxel induced metabolic stress,
males but not females experienced anti-nociception in response to PPAR-alpha signaling. This is
concurrent with a downregulation of PPAR-alpha after paclitaxel treatment in the DRG,
suggesting males and females utilize different metabolic pathways for anti-nociception. Our final
study involved the role of cannabinoid receptor one (CB1R) in Nav1.8-containing neurons.
Canonically, CB1R reduces cellular energy expenditure via the Gi/o pathway; it has also been
established as effective in reducing both chronic and acute pain, but it is unclear what cell is
responsible for this phenomenon. To investigate this, we utilized a novel model where CB1R is
only present on Nav1.8-contaning neurons (CB1RNav1.8) and exposed animals to a variety of
behavioral experiments. Interestingly, we found males and females responded similarly to CB1R
agonism, increasing the desirability of the target for pain relief. CB1RNav1.8 and knockout
animals behaved similarly in inflammatory pain experiments, and CB1RNav1.8 and wildtype
animals behaved similarly in neuropathic pain experiments. These data suggest CB1R in neurons
mediate nociception differently based on the source of insult, and CB1R on immune cells may be
more responsible in mediating inflammatory pain. Our data lay the foundation for sex-specific
and sex-independent peripheral signaling pathways, continuing to establish peripheral
mechanisms for more targeted therapeutics
Micromachined Acoustic Transducers With Embedded Vertical Capacitive Arrays
No full textAcoustic transducers are the crucial interface between acoustic signals and electrical signals, playing a pivotal role in converting and manipulating sound waves for a wide range of applications across industries and healthcare, such as non-destructive evaluation, range finding, proximity sensing, ultrasonic actuation and sensors, medical imaging probes, therapeutic ultrasound, microphones, and micro speakers. Such applications require transducers operating at frequencies spanning from tens of hertz to hundreds of megahertz. For most of the applications, generating strong acoustical signal is the most important design parameter. Achieving strong acoustic signals and heightened sensitivity demands a high output pressure per transducer unit area. To generate high output pressure per transducer unit area, higher vibration amplitude is required. When a transducer vibrates with a large vibrational amplitude, it can generate high output pressure per surface area even at a lower frequency. For example, when an acoustic membrane generates high output pressure per surface area, it would enable the membrane to produce enough audible sound at low frequency and works as a low frequency speakers or hearing aid instruments. Over the past century, acoustic transducer technology has evolved from piezoelectric crystals to contemporary
capacitive micromachined ultrasonic transducer (CMUT) or piezoelectric micromachined ultrasonic transducer (PMUT). However, current piezoelectric or electrostatic micromachined transducer face design and fabrication limitations for generating substantial vibration amplitudes.
The main objective of this work is to demonstrate a novel approach that transforms the electrostatic transduction that is conventionally performed by a closely spaced electrode next to the vibrating membrane to an array of electrostatic cells embedded within the membrane. The air gap between the fixed electrode and moveable membrane of the conventional electrostatic acoustic transducers limits the vibration amplitude in the range of tens of nm to few microns. Expanding this gap further is restricted by concerns related to reliability, difficulties in fabrication, and the need for higher operating voltages. The array structures of this research can bypass all the above-mentioned issues and enable the realization of ultrasonic transducers and microspeakers with large out-of-plane displacement, resulting in high sound pressure output per unit area at moderate operating voltage. Extremely narrow air gaps can be made in the vertical electrostatic cells which allows the devices to be operated at low operating voltage while generating high electrostatic force and energy per unit area. Electrostatic cells embedded within the membrane also facilitate the membrane to vibrate with much larger vibration amplitude compared to the conventional devices.
Using this novel approach, an acoustic membrane operating in the audible range has shown almost 5 times higher output pressure per surface area per volt compared to the state-of-the-art. Smaller membrane with a resonance frequency in the ultrasonic range would have much higher output pressure per surface area compared to the conventional CMUT and PMUT. This approach can also be used to design a much stronger MEMS micropump for drug delivery, and other MEMS devices where vibrating membrane is the crucial part
The Future of Zirconia as an Alternative Biomaterial for Dental Implant Systems: A Comprehensive Evaluation of Its Biological, Mechanical, and Surface Properties
No full textDental implants are some of the most common and successful implantable devices with
approximately 800,000 procedures being performed annually in the US alone. Titanium has
served as the material of choice for dental implants since the discovery of its ability to undergo
osseointegration with bone tissue. However, titanium dental implants can inevitably fail for a
plethora of reasons including bacterial infection, excessive cyclic loading, failure to achieve or
loss of implant stability, surgical trauma, and patient-related complications. Many failure modes
associated with titanium dental implants stem from the material itself which can degrade via
corrosion-mediated mechanisms in the oral cavity. Ultimately, this can result in the generation
and accumulation of toxic metal ions and debris in the host tissue, triggering an inflammatory
cascade leading to eventual implant loss. To avoid problems associated with metallic
biomaterials, zirconium oxide, also known as zirconia, has been explored as an alternative
material comprising the entire dental implant system. As a ceramic, zirconia exhibits properties
including mechanical strength and osseointegration desirable for dental implant applications
while also possessing immunity to corrosion, an esthetically appealing ivory white color, and
lower plaque accumulation as opposed to titanium. Despite these advantages and promising
results from short-term clinical data, the material behavior and response of zirconia to the same
oral environmental factors including bacterial adhesion and mechanical fatigue that deteriorate
titanium surfaces remain understudied. Therefore, the goal of this study was to systematically
assess the biological and mechanical properties of zirconia as compared to titanium when
subjected to oral environmental factors including bacterial biofilm and fatigue-inducing cyclic
stresses and their impact on zirconia surface degradation. Based on preliminary data, it was
hypothesized that the biological response to zirconia would be equivalent to or better than that on
titanium while the mechanical performance of zirconia would become compromised depending
on prior surface treatment and environmental conditions. To test these hypotheses, this project
was divided into two aims. Aim 1 investigated the “race-for-the-surface” between mammalian
host tissue cell attachment and oral bacterial biofilm growth in mono- and co-culture on zirconia
to understand its effect on the outcome for soft tissue healing and osseointegration of zirconia.
Afterward, aim 2 focused on characterization of potential degradation conditions of zirconia after
exposure to biological milieu, namely bacterial adhesion and cyclic mechanical loading under
individual and synergistic test conditions simulating mastication (chewing) and oral
environment, to determine which factors accelerate degradation of zirconia surfaces.
Accomplishing the aims of this proposal yielded new knowledge about the material performance
of zirconia which can provide guidance on the design of future zirconia-based dental and related
implant systems
Metronidazole Degradation by the Gram-positive Bacterium Enterococcus Faecalis
No full textEnterococcus faecalis is a species of Gram-positive bacterium that natively inhabits the human
gastrointestinal tract. This bacterium is capable of causing sepsis and endocarditis and is
associated with the decreased effectiveness of antibiotic treatments for other bacterial infections.
One such antibiotic is metronidazole, a 5-nitroimidazole drug once used commonly in the
treatment of Clostridioides difficile infections. We hypothesize that E. faecalis reduces the
efficacy of metronidazole in treating C. difficile infections. The molecular mechanism for how E.
faecalis degrades metronidazole is unknown. In this work, we demonstrate how different strains
of E. faecalis affect levels of metronidazole in in vitro culture. Through the use of
spectrophotometry, we screened for E. faecalis transposon mutants unable to degrade
metronidazole and used DNA sequencing to determine the insertion sites of the transposons.
Screening has yielded two E. faecalis strains of interest, dubbed E. faecalis A7 and E. faecalis
H8. These strains have disruptions in genes that encode the proteins AroA and AroB,
respectively, which indicates that the chorismate synthesis pathway is crucial to E. faecalis’s
ability to degrade metronidazole. These data lead us to propose that E. faecalis utilizes extracellular electron transfer to degrade metronidazole, a process that relies on a reliable supply
of chorismate to synthesize demethylmenaquinone. This compound, alongside other membrane
proteins, is utilized in extracellular electron transfer in E. faecalis. Since the reduction of
metronidazole to a toxic form is seen in C. difficile, we theorize that E. faecalis uses extracellular
electron transfer to reduce metronidazole to a different compound that is non-toxic to bacteria. In
summary, we hypothesize that the work of demethylmenaquinone and other extracellular
electron transfer proteins is the link behind E. faecalis and metronidazole degradation due to the
nature of extracellular metronidazole reduction mechanisms that exist in Gram-positive bacteria
EphrinB2 Mediation of EphB Dependent Nociceptive Plasticity Through the MNK-eIF4E Signaling Axis
No full textChronic pain types often exist as a manifestation of overconnectivity after
Sustaining an injury. The molecular mechanisms that govern this transition from
Acute to chronic pain is largely unknown. The ligand EphrinB and its primary
receptor, the EphB family of receptor tyrosine kinases is fundamental in the
formation of homeostatic functions, including angiogenesis, axonal guidance, and
synaptic adherence. The mechanisms that govern these functions are largely
unknown in the context of pain. Our laboratory has previously demonstrated the
involvement of extracellular kinase phosphorylation events at specific tyrosine residues
residue phosphorylated the EphB2 receptor to engage the NR2B subunit of the
NMDA receptor to initiate pain hypersensitivity in the dorsal horn of the spinal cord
cord in rodents through EphrinB2 administration. Therefore, I hypothesized that
The interaction between EphrinB2 and EphB2 in the peripheral nervous system may be involved
in peripheral sensitization to initiate central sensitization in the dorsal horn and
reveal the downstream mechanistic target of this signaling cascade. I have
uncovered EphrinB2 is sufficient to induce peripheral sensitization in a
dependent manner driven by phosphorylation of eIF4E through MNK. EphrinB2
initiates both mechanical hypersensitivity and thermal hyperalgesia in males, but
only mechanical hypersensitivity in females. Furthermore, we found both sexes
experience hyperalgesic priming through prostaglandin E2 and is blocked through
MNK activity. To discern which neuronal population is responsible for these
behavioral effects, we used an EphB2-Pirt mouse line to demonstrate the loss of
nociceptive behaviors and priming initiation. Molecularly, pre-treatment
of EphrinB2 in vitro to demonstrate the ability of ligands to initiate priming
calcium imaging and alterations in latency to peak We confirmed these findings
are translatable in human in vitro models in which the blockade of priming responses
through the MNK inhibitor eft508 and subsequent decreases in peIF4E levels
treatment. Together, these findings indicate a novel role for EphrinB2–EphB2
family in the context of pain and characterize nociceptive behavioral differences
between the sexes and unveils a key downstream signaling target that is necessary for
initiate these effects between species