VictorJuiz/thesis huggingface dataset:
Rescuing Dopamine Transporter Deficiency Syndrome
Keywords: bupropion
dopamine
dopmaine transporter
Dopmaine transporter deficiency syndrome
noribogaine
structure activity relationship

The dopamine transporter (DAT) is a membrane protein essential to dopamine homeostasis. Abnormal dopamine homeostasis is implicated in multiple conditions including the newly discovered dopamine transporter deficiency syndrome (DTDS). DTDS is an autosomal-recessive disorder caused by mutations that impair DAT maturation. Bupropion and ibogaine can rescue DTDS DAT mutants. We therefore examine the structure-activity relationships responsible, in hopes of discovering more efficacious and potent compounds. An SAR-based screen of bupropion and ibogaine analogs demonstrated necessity for a secondary amine and single halogen substitution on bupropion along with a flexible heterocyclic ring, chair-like substituent and hydroxyl substitution on ibogaine. Lead candidates noribogaine and PAL594 were able to rescue mature DAT. We also report that there is no link between DAT inhibition and chaperoning, suggesting that chaperoning is mediated allosterically. Future studies should aim to validate the presence of the putative DAT allosteric site, computer-assisted drug discovery and a mouse model.
Epithelial Cells Exhibit Dynamic Filopodia During Zebrafish Epiboly
Keywords: Cell Protrusions
Epiboly
Filopodia
Gastrulation
Zebrafish

Initially, the zebrafish embryo consists of a cell mass (blastoderm) atop a large yolk cell. During gastrulation, epiboly is the process whereby the blastoderm thins and spreads downwards to enclose the yolk. The blastoderm comprises an outer epithelium, the enveloping layer (EVL), and inner deep cells (DCs). The EVL stretches during epiboly, while the DCs undergo cell rearrangements. I observed cellular protrusions between EVL and DCs and investigated their potential role in facilitating epiboly. I classified the protrusions as filopodia by using actin markers and examined their spatio-temporal dynamics by live imaging. Filopodia were found throughout the EVL and in the largest number during early epiboly at the animal pole, where DC rearrangements are greatest. In functional studies, expression of a constitutively active actin bundling protein resulted in increased EVL filopodial length and delayed epiboly. These results suggest that EVL filopodia may function during early epiboly to promote DC rearrangements.
Design and Optimization of Nanoparticulate Permeability-Modifiers for pH-independent Drug Release and Alcohol-resistant Dosage Forms
Keywords: Alcohol resistance
Coated dosage forms
Ethylcellulose
pH-responsive nanoparticles
Pore formers
Terpolymer

Most drugs on the market are either weakly basic or weakly acidic. Their pH-dependent solubility may result in undesired drug release kinetics of modified-release dosage forms (MRDFs) due to the food and/or drug-induced effect on gastrointestinal pH. Moreover, co-ingestion of alcohol with MRDFs of opioids has posed a high risk of dose dumping and drug toxicity. This thesis thus aims to design nanoparticulate permeability modifiers to mitigate these problems. For pH-independent drug release, a pH-responsive starch-based terpolymer nanoparticle (TPN) system incorporated in ethylcellulose (EC) developed by our group was optimized using a central composite design (CCD). The incorporation of TPNs in EC was able to modulate local pH within the matrix to increase permeability and solubility of basic drugs. Alcohol-insoluble and non-swellable nanoparticle compositions were designed using CCD to compensate for the high solubility of ethylcellulose coating in alcohol and exhibited improved processability compared to the current alcohol-resistant coating technology.
Individual Differences in Autobiographical Memory and Their Relationship to Cognitive Aging
Keywords: aging
autobiographical memory
individual differences

Individuals differ in how they remember the past: some recall the gist of an event, whereas others re-experience specific details. While memory decline is a hallmark of cognitive aging, trait-level individual differences in memory abilities have received little consideration in aging research. Given the functional decline that accompanies memory deficits, one might expect that strong native episodic memory is protective—but we hypothesized that individuals with lower episodic memory abilities would report less age-related functional decline. We reasoned that those who have relied on congenitally strong episodic memory throughout life must newly adjust to age-related memory decline, whereas those with lower episodic memory abilities enter aging prepared with compensatory strategies. We tested a large sample of older adults online and found, as predicted, that lower self-reported episodic memory abilities were associated with less age-related functional decline. These findings emphasize the importance of considering individual differences when studying cognitive aging trajectories.
The Generation of Extremely Fine Water-in-Bitumen emulsions via the Satellite Drop Formation Mechanism
Keywords: Drop Breakup
Froth Treatment
Satellite Drops
Water-in-bitumen emulsions

This thesis is concerned with the generation of fine water-in-bitumen emulsions through drop fracture during the bitumen froth treatment process. Due to their negative economic and environmental impact, the stability of these emulsions has received tremendous attention; however, little work has been conducted on the manner through which they form. In this study, we use a novel microfluidic platform to study the satellite drop generation mechanism via drop fracture. Using this technique, satellite drops several orders of magnitude smaller than the mother drop were generated and characterized. The smallest satellite drops observed were below 2μm in radius. The range of satellite. The effects of industrially relevant parameters, namely, water pH, solvent dilution and capillary number, are investigated. The satellite drop volume and number of drops were found to increase with the capillary number and dilution while process water pH was found to have a smaller effect.
The effect of nucleic acid-binding ligands on CTG/CAG repeat DNA metabolism in vitro
Keywords: DNA ligand
Huntington's Disease
Mismatch repair
Myotonic Dystrophy
Slipped-DNA
Triplet repeat

CTG/CAG repeat expansions cause at least 16 neurodegenerative and neuromuscular diseases. Unusual DNA slip-out structures that form in CTG/CAG repeat tracts have been implicated in the expansion process; targeting these structures may be of therapeutic benefit. In vitro assays can be used to screen for DNA-binding molecules that specifically target disease-associated slip-out structures and therefore potentially modulate expansions. Toward establishing tool compounds, we characterized the effects of ethidium bromide and actinomycin D on repeat DNA metabolism in vitro. Both tool compounds preferentially bound certain CTG/CAG structures over others, consistent with the varying efficiencies with which they inhibited the repair of different slip-out substrates. Additionally, I screened small molecules designed to bind RNA repeat disorder sequences, which are suggested lead compounds. Multiple compounds inhibited slipped-DNA repair, marking them as potential modulators of instability. However, the same compounds also inhibited G-T base-base mismatch repair, indicating possible off-target, genotoxic effects.
Relationship between TAR DNA-Binding Protein 43 Phosphorylation and Stress Granules: Implications for Amyotrophic Lateral Sclerosis
Keywords: ALS
immunocytochemistry
neurodegeneration
phosphorylation
stress granules
TDP-43

Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons in the brain and spinal cord, and is pathologically typified by cytoplasmic inclusions containing TAR DNA-binding protein 43 (TDP-43) in degenerating neurons. TDP-43 is a nuclear DNA/RNA-binding protein that is recruited to stress granules, which triage translationally stalled pre-initiation complexes, promoting expression of mRNAs necessary for cell survival. TDP-43 is abnormally phosphorylated in ALS, the role of which in relation to stress granule dynamics has not been widely explored. Here, I examined various stresses in three different cell lines and used immunocytochemistry to assess stress granule formation and TDP-43 localization. My results demonstrate that recruitment of TDP-43 to stress granules is context-dependent. I then explored the relationship between TDP-43 phosphorylation and stress granules through the generation of phosphorylation mutants. Intriguingly, hyperphosphorylation of TDP-43 prevented its recruitment to stress granules, in vitro.
Stereotype Maintenance through Approach-Contingent Information Gain
Keywords: avoidance
stereotyping

Research on stereotype formation has proposed a variety of reasons for how inaccurate stereotypes arise, focusing largely on accounts of motivation and cognitive efficiency. Here, we instead consider how stereotypes arise from the asymmetrical manner in which information is sampled from the environment. Examining group-based generalizations in the context of approach/avoid decisions, we propose that initial negative interactions with a few group members cause subsequent avoidance of the entire group, even when these interactions are unrepresentative of the group overall. Critically, as information gain is contingent on approaching the target, such avoidance leads to a failure to update one’s beliefs about the group, even when the group has drastically changed. 9 studies provide support for these hypotheses, demonstrating that approach-contingent information gain results in failures to accurately update beliefs about initially negative groups. We also present initial results of computational models that test whether negative representations are reinforced by avoidance.
Investigating the role of autophagy in Arabidopsis self-incompatibility
Keywords: Arabidopsis
Autophagy
Brassicaceae
Pistil
Pollen
Self-incompatibility

In the flowering plants, fertilization is controlled by a series of interactions between pollen and pistil. Members of the Brassicaceae have dry stigmas, allowing for strict regulation of pollen acceptance through the selective hydration and germination of compatible pollen grains. Many species within this family have also maintained an outcrossing mechanism, known as self-incompatibility (SI), where self-pollen is rapidly rejected at the stigma surface by preventing pollen hydration and pollen tube entry into the stigma. This thesis investigated the putative role of autophagy in SI using the inbreeding species Arabidopsis thaliana transformed with Arabidopsis lyrata SI genes as the model system. Furthermore, ecotype variation in the SI response was investigated by studying the autophagy response in Col-0 and C24. Overall, I found that both ecotypes displayed activation of autophagy in the stigma with SI pollinations. Thus, autophagy is a conserved SI response in both A. lyrata and A. thaliana.
PAR2 activation increases α-synuclein expression, aggregation and phosphorylation in human oligodendrocytes with emphasis on pathophysiology of Multiple System Atrophy (MSA)
Keywords: MO3.13
Multiple System Atrophy
Oligodendrocyte
PAR2
Proteinase Activated Receptor2
western blot

The proteinase activated receptors (PARs) are a novel family of G protein–coupled receptors. Previous reports suggested the involvement of PAR2 signaling in neurodegenerative disorders. However, a role for PAR2 in Multiple System Atrophy, an adult onset sporadic neurodegenerative disease, has not been addressed. Aggregates of α-synuclein in the cytoplasm and in the nucleus of oligodendroctyes pathologically characterize this disease. I hypothesized that stimulation of PAR2 signaling increases α-synuclein expression, aggregation and phosphorylation. The results of current research show that stimulation of PAR2 receptor by three specific agonists, results in MAP Kinase (P42/44) phosphorylation and activation of the downstream pathways. Changes in α-synuclein monomer concentration and aggregation as well as phosphorylation in MO3.13 cells as the downstream effects of PAR2 activation can be correlated to MSA disease. These results may identify a potential therapeutic target upstream of α-synuclein aggregation and toxicity to prevent progression of multiple system atrophy.
Selective attention during encoding mediates memory representation
Keywords: attention
cognition
episodic memory

Attention selects the information we remember, yet the specific mechanism by which attention influences our memory remains unclear. This investigation examined a novel interpretation of how attention and memory interact: whether semantic vs. perceptual attention biases the encoding of precise-integrated representations that constrain the detail of our memories. I present two studies that examine how semantic vs. perceptual attention to illustration features impacts representation. Participants attended to perceptual or semantic features at encoding, then performed a surprise memory test for the illustrations. Study 1 showed that perceptual attention led to precision from experiences with the attended feature. Study 2 examined if perceptual attention facilitated precision for the attended feature, or overall. Memories showed precision from perceptually similar experiences and integration with semantically similar experiences, irrespective of attention state. Further work is needed to determine whether mnemonic precision and integration is biased across semantic and perceptual attention tasks.
Breast Tumorigenesis Associated with BRCA1 Deficiency is Dependent on RNF8
Keywords: BRCA1
Breast Cancer
DNA Damage
RNF8

Defects in DNA damage repair result in genomic instability; a process that has been recognized as a driving factor in the development of several types of cancer. RNF8 and BRCA1 are E3 ubiquitin ligases that play crucial roles as tumor suppressors by mediating cellular responses to DNA double strand breaks (DSBs). In animal models, we have found that Rnf8 and Brca1 deficiencies predispose mice to the development of mammary tumors. Interestingly, Rnf8-/-;WapCre;Brca1fl/fl double mutant mice are protected from mammary tumorigenesis. Data collected in this study suggests that Rnf8-/- ;WapCre;Brca1fl/fl double mutant mice are protected from tumorigenesis due to a unique synthetic lethal-like interaction between RNF8/Rnf8 and BRCA1/Brca1. We propose that RNF8 inhibition should be investigated further as a potential therapeutic target for the treatment of BRCA1-associated breast cancer.
Imaging alterations in endocannabinoid metabolism in clinical high risk for psychosis: The first cohort of a PET study using [11C]CURB
Keywords: [11C]CURB
clinical high risk
endocannabinoid
fatty acid amide hydrolase
PET imaging
psychosis

The endocannabinoid (eCB) system mediates responses to cannabis and stress, both risk factors for psychosis. Individuals at clinical high risk for psychosis (CHR) exhibit sensitivity towards stress and cannabis. Evidence support an alteration of the eCB system in psychosis. Here, we measured brain levels of FAAH, the degradative enzyme of the major eCB anandamide, in CHR using the novel PET radioligand [11C]CURB. We recruited 20 controls and 23 CHR. Participants underwent [11C]CURB PET and MRI scans. Regional [11C]CURB binding was calculated using an irreversible 2-tissue compartment model. Analysis revealed no significant difference between [11C]CURB binding in CHR and controls (F(1,39)=2.541; p=0.119). There were significant correlations between [11C]CURB binding and scores of depression, trauma, and cannabis use across brain regions (p>0.05). These preliminary results suggest that FAAH is not altered in CHR. There might be a role for depression, trauma, and cannabis use on FAAH in CHR.
The Role of DNA Damage-induced Cellular Senescence in the Pathophysiology of mTBI
Keywords: Chronic Traumatic Encephalopathy
mTBI
Neurodegenerative Disease
Senescence
Traumatic Brain Injury

The pathophysiological mechanism whereby mTBI leads to chronic symptoms and neuropathology is unknown, although it is known that cellular senescence underlies several neurological disorders. I hypothesize that mTBI causes DNA damage-induced cellular senescence, leading to the acute and chronic neurological dysfunction reported in individuals who have suffered from mTBI. Using a cohort of 38 donated brains with mTBI history, I have found extensive DNA damage with immunohistochemistry (γH2AX, a marker of double-stranded DNA breaks) not seen in control brains. Furthermore, gene expression analysis using NanoString revealed activation of DNA damage response pathways, insufficient expression of DNA repair proteins, and upregulation of pro-inflammatory and cellular senescence pathways. This study suggests that DNA damage-induced cellular senescence may be the underlying pathophysiological mechanism of acute and chronic brain dysfunction after mTBI, and represents potential therapeutic targets for treatment of mTBI-induced brain dysfunction.
Repopulation of De-epithelialized Tracheal Grafts
Keywords: airway epithelium
de-epithelialization
mechanical stimuli
re-epithelialization
shear stress
trachea

Pathologies affecting more than 50% of the tracheal length usually require functional replacements. Engineered biological scaffolds are a promising alternative for tracheal transplantation. However, epithelial cells have not shown efficacious cell-scaffold interactions or functionality, thus limiting graft success. Without successful epithelialization, the trachea is liable to stenosis, collapse, fibrosis, and infections. The effect of mechanical cues on tracheal epithelial cells is not well known. This project aims to optimize the repopulation of tracheal scaffolds by defining the mechanical cues for adequate adherence, growth, and proliferation of the epithelium. We have engineered an adequate homogeneous airway BEAS-2B epithelium in long-segment tracheal grafts obtained by decellularization of donor tracheas harvested from Yorkshire pigs. The decellularized grafts were successfully repopulated inside a purposely designed double-chamber, rotating, automated bioreactor using a bidirectional perfusion cell seeding protocol, followed by unidirectional flow for the culture phase. Results show that shear stress has statistically significant effects on cell attachment and metabolic cell activity, with better outcomes observed in low-shear stress cases. Overall, the resulting seeding protocol allows repopulation of tracheal grafts, with uniform scaffold coverage and a confluent epithelium that is metabolically active and viable.
The Role of the Microbiome-gut-brain Axis in Schizophrenia and Clozapine-induced Weight Gain
Keywords: Clozapine
Gut Microbiome
Gut-brain axis
Schizophrenia
Weight Gain

The gut microbiome (GMB) plays an important role in developmental processes and has been implicated in the etiology of psychiatric disorders. However, the relationship between GMB and schizophrenia is poorly defined. We analyzed fecal samples from 25 schizophrenia patients chronically treated with clozapine (CCLZ) and 9 healthy controls (HCs). Alpha diversity and Beta diversity analyses showed no significant differences at multiple sequencing depths between CCLZ and HCs. The relative abundance of the phylum Proteobacteria and class Gammaproteobacteria was observed to be increased in schizophrenia patients taking CLZ. However, no significant differences were found at other taxa levels. Gram-negative bacteria (Proteobacteria) produce LPS which has been implicated in various schizophrenia models and contribute to the development of a leaky gut and inflammation, commonly seen in patients with schizophrenia. This study helps lay the groundwork for further investigations into the role of the GMB in the development, presentation and progression of schizophrenia.
New Methods for Tracking the Photocatalytic Efficiency of BiOX and TiO2 Nanocomposite Materials using NMR
Keywords: Photocatalysis
Photocatalytic Intermediate Identification
Photocatalytic Mechanism

Photocatalysis has been proposed as a green method of solving environmental and human health related issues such as wastewater treatment, anti-microbial treatment, and development of self-cleaning surfaces. Despite thousands of papers on photocatalytic materials and theory, photocatalytic materials have not been able to redefine our industrial landscape as once thought. I will describe the synthesis and characterization of new highly efficient photocatalytic materials, nanoplate- BiOCl and TiO2-NGQD nanocomposites. Further traditional methods, such as UV-Vis, TOC, and LC-MS, for evaluating efficiency and their shortcomings will be discussed. Finally, novel work in using NMR to track photocatalytic reactions and its potential to glean new insight into the mechanism is shown.
Adrenergic Control of Lymphatic Drainage from the Eye
Keywords: Adrenergic Receptors
Autonomic Nervous System
Glaucoma
In Vivo Imaging
Lymphatics

Aqueous humour is a clear fluid that nourishes the eye's anterior segment. It drains from the eye via the conventional, uveoscleral pathway, and lymphatics. It is well established that the sympathetic system adrenergic receptors modulate lymphatics in other organs. However, ocular lymphatics remain to be explored. Glaucoma is a blinding disease associated with high IOP. Currently, all glaucoma medications reduce IOP by decreasing aqueous production or increasing outflow. However, glaucoma medications effects on the lymphatic pathway are not yet known. Using non-invasive in vivo photoacoustic imaging approach, the effect of two glaucoma medications, timolol and brimonidine, was quantified. Timolol, a ß-adrenergic blocker, significantly reduces ocular lymphatic drainage. In contrast, brimonidine, an α2-adrenergic agonist, significantly increases it. Finally, lymphatic channels in the eye were positive for adrenergic receptors. These findings provide the first evidence for adrenergic control of ocular lymphatics and may be relevant to understanding glaucoma care to prevent blindness.
Developing New Algorithms to Assess the Effectiveness of Mandibular Advancement Devices for the Treatment of Sleep Apnea
Keywords: Mandibular Advancement
Obstructive Sleep Apnea

Mandibular advancement is a treatment for obstructive sleep apnea (OSA). The issue with this treatment is that it's hard to predict responders. We performed a systematic review of previous literature and examined the effects of clinical, craniofacial, and pharyngeal airway features to predict responders to mandibular advancement. Some studies suggested that a retruded mandible and smaller width of the oropharynx were the main characteristics of responders to mandibular advancement. However, other studies found that these features didn't differ between responders and non-responders. The second objective of this study was to find additional features that assess the response to mandibular advancement. We investigated the effect of mandibular advancement on snoring sound and sleep features. We found that mandibular advancement decreased the snoring intensity and reduced the apnea duration in the supine position. These findings suggest that mandibular advancement could improve other measures of sleep quality including snoring intensity and apnea duration.