VictorJuiz/thesis huggingface dataset:
The Functional Significance of Oscillatory Activities in the Basal Ganglia and Pedunculopontine Nucleus Region in Parkinson’s Disease and Dystonia
Keywords: Movement disorders
Neurophysiology
Basal ganglia
Deep brain stimulation

Parkinson’s disease (PD) and dystonia are movement disorders related to dysfunctions of basal ganglia (BG). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and internal globus pallidus (GPi) are treatments for PD and dystonia. Previous research indicated that abnormally elevated oscillatory activities at the theta (3-10 Hz) beta frequency bands (11-30 Hz) may be related to parkinsonian and dystonic motor symptoms but their precise roles are not well understood. Recently, DBS of the pedunculopontine nucleus region (PPNR) has been used to treat PD patients with postural and gait dysfunctions, but movement-related PPNR activities had not been explored. We aimed to investigate movement-related local field potentials (LFP) recorded from the BG and PPNR in PD and dystonia patients. We recorded STN LFP from PD patients and subsequently applied the intrinsic STN theta, beta, and gamma (31-100 Hz) frequencies through DBS to study their effects on PD motor signs. We also recorded movement-related PPNR LFP in PD patients and movement-related GPi activities in patients with primary dystonia. Finally, we simultaneously recorded movement-related activities from the GPi and the motor thalamus in a patient with secondary dystonia. We found that DBS at the dopamine-dependent and movement-related intrinsic STN gamma frequencies, were as effective as traditionally used high frequencies (130-185 Hz) in reducing PD motor signs, but theta and beta frequencies did not worsen motor symptoms. Voluntary movements modulated two discrete movement-related frequencies in the theta and beta bands in the PPNR and these two frequencies interacted with the sensorimotor and frontal cortices during movements. We showed that voluntary movements modulated beta and gamma frequencies in the GPi. A resting ~5-18 Hz coherence between the GPi bilaterally was attenuated during movements in patients, which may be related to dystonia because this 5-18Hz coherence was also present between the GPi and motor thalamus in the patient with secondary dystonia. Our findings indicated that intrinsic STN gamma frequency oscillations were likely prokinetic rhythms but theta and beta frequencies may not contribute to PD motor symptoms. Voluntary movements modulated theta and beta frequencies in the PPNR, which may explain why PPNR DBS uses lower frequencies than those of the BG. The 5-18 Hz oscillatory activities in the BG-thalamic circuit may be a feature of dystonia.
Study of Blast-induced Damage in Rock with Potential Application to Open Pit and Underground Mines
Keywords: borehole blasting
seismic waves
blast-induced damage
direct and reverse initiation of explosive
seismic radiation
rock excavation
FEM-DEM
stress waves
PPA
PPV
blast-induced seismicity
Y2D
blast experiments
rock fracturing
crack density
direct and reverse initiation of explosive
seismic waves superposition

A method to estimate blast-induced damage in rock considering both stress waves and gas expansion phases is presented. The method was developed by assuming a strong correlation between blast-induced damage and stress wave amplitudes, and also by adapting a 2D numerical method to estimate damage in a 3D real case. The numerical method is used to determine stress wave damage and provides an indication of zones prone to suffer greater damage by gas expansion. The specific steps carried out in this study are: i) extensive blast monitoring in hard rock at surface and underground test sites; ii) analysis of seismic waveforms in terms of amplitude and frequency and their azimuthal distribution with respect to borehole axis, iii) measurement of blast-induced damage from single-hole blasts; iv) assessment and implementation of method to utilize 2D numerical model to predict blast damage in 3D situation; v) use of experimental and numerical results to estimate relative contribution of stress waves and gas penetration to damage, and vi) monitoring and modeling of full-scale production blasts to apply developed method to estimate blast-induced damage from stress waves. The main findings in this study are: i) both P and S-waves are generated and show comparable amplitudes by blasting in boreholes; ii) amplitude and frequency of seismic waves are strongly dependent on initiation mode and direction of propagation of explosive reaction in borehole; iii) in-situ measurements indicate strongly non-symmetrical damage dependent on confinement conditions and initiation mode, and existing rock structure, and iv) gas penetration seems to be mainly responsible for damage (significant damage extension 2-4 borehole diameters from stress waves; > 22 from gas expansion). The method has the potential for application in regular production blasts for control of over-breaks and dilution in operating mines. The main areas proposed for future work are: i) verification of seismic velocity changes in rock by blast-induced damage from controlled experiments; ii) incorporation of gas expansion phase into numerical models; iii) use of 3D numerical model and verification of crack distribution prediction; iv) further studies on strain rate dependency of material strength parameters, and v) accurate measurements of in-hole pressure function considering various confinement conditions.
Derivation of an Appropriate Outcome Measure in Lupus
Keywords: Lupus
Outcome measure

Aim: To develop an outcome measure to identify “responders” for patients who had a clinically important improvement in lupus disease activity with treatment. Methods: The outcome measure derived was based on the commonly used disease activity measure SLEDAI-2K which documents findings over the previous 10 days. Since patients in drug trials are followed at monthly intervals it was necessary to validate SLEDAI-2K 30 days against SLEDAI-2K 10 days. Two prospective studies were accomplished for this purpose. SLEDAI-2K 30 days was used to develop the new responder index, SLEDAI-2K Responder Index-50 (SRI-50). The SRI-50 data retrieval form was developed to standardize the documentation of the descriptors. The construct validity of SRI-50 was prospectively evaluated against an external construct. The reliability of SRI-50 was tested in a multi-centre study. A retrospective analysis over 10 years was used to further validate SRI-50. SRI-50 ability to enhance the SLE Responder Index (SRI) in detecting “responders” was evaluated. The performance of SRI-50 was investigated against SLEDAI-2K and SRI over 12 months. Results: SLEDAI-2K 30 days was validated to describe disease activity over the previous 30 days. The responder index to SLEDAI-2K, SRI-50 was developed including the SRI-50 Definitions and SRI-50 Data Retrieval Forms. The initial validation of SRI-50 confirmed its construct validity to identify ≥ 50 % improvement. SRI-50 is reliable and can be used by both rheumatologists and trainees. The retrospective analysis confirmed that SRI-50 is valid in identifying ≥ 50 % improvement in an efficient time. SRI-50 enhances the performance of SRI and identifies more “responders” than SLEDAI-2K and SRI at 6 and 12 months. Conclusions: SRI-50, is a valid and reliable responder index to identify patients with partial, ≥50% improvement in disease activity in an efficient time. SRI-50 can be used as an independent outcome measure of improvement in patients with SLE.
Functional Roles of the SWI/SNF ATPase Brahma Related Gene 1 (BRG1) and Special AT-Rich Binding Protein (SATB1) in Virus Response and Innate Immunity
Keywords: BRG1
SATB1
Interferon
Innate Immunity

The innate immune response is a primary transcriptional defence network activated by interferons (IFNs) α/ β in response to viral infection. A cell must have the capability to detect the virus, activate signalling cascades, and engage transcriptional anti-viral networks. IFNs trigger the Signal Transducer and Activator of Transcription (STAT) family, which in turn induce anti-viral gene expression. Recruitment of STATs to IFN stimulated gene (ISG) promoters and the ensuing gene induction requires Brahma Related Gene 1 (BRG1), the catalytic component of the SWI/ SNF chromatin remodelling (or BAF) complex. Cell lines with high BRG1 expression are hyper-responsive to IFN induced transcription, conversely BRG1 low cells exhibit impaired induction. However, BRG1 high cells that are resistant to Encephalomyocarditis virus infection did not require signalling through the IFN receptor complex for anti-viral immunity. This suggested 2F-BRG1 cells must rely on BRG1 dependent non-ISGs or an as yet uncharacterized subset of basally expressed BRG1-dependent ISGs that do not require IFN enhanced expression for anti-viral activity. Utilizing genome wide microarrays we identified five genes with potent anti-viral activity. These genes may restrict viral infection through alterations in integrin signalling, endosomal trafficking, and activation of host transcriptional responses. We also investigated the role of Special AT-Rich Binding Protein (SATB1) in regulation of IFN responsive genes. The loss of this chromatin binding protein is associated with transcriptional changes in the MHC locus that mimic IFNγ induced expression. Through microarray analysis we discovered a remarkable 47% of IFNα regulated genes were co-regulated by SATB1; 42% of IFNα induced genes were induced by SATB1 knock down, while 63% of IFNα repressed genes were SATB1 dependent. Functionally, knock down of SATB1 protected cells from EMCV induced cell death at low multiplicity of infection (MOI), and increased the cytoprotective effect of IFNα against EMCV at higher MOIs. Analysis of IFNα, SATB1 and BRG1 regulated genes revealed a subset of core genes regulated by all three factors that may be critical to robust anti-viral immunity. The potent immunosuppressive properties of SATB1 suggest this protein may be involved in complex immunopathologies. The immuno-modulatory properties of SATB1 and BRG1 established in this thesis provide substantive evidence for the development of pharmaceutical therapies targeting these proteins.
Aeta Women Indigenous Healers in the Philippines: Lessons and Implications
Keywords: Aeta women healers
Aeta people
Indigenous knowledge production
talking circle
Indigenous healing
public health
anti-colonial theory
post-colonial theory
colonization
Indigenous feminism
decolonizing methodologies
participatory action research
race
class
gender
identity
agency
representation
subalternity
ethno-medicine
pre-colonial and colonial Philippines history
spirituality
worldview
inequality
prejudice
sociology of health and Indigenous health

This study investigates two central research problems. These are: What are the healing practices of Aeta women? What are the implications of the healing practices of Aeta women in the academic discourse? This inquiry is important for the following reasons: (a) it focuses a reconsidered gaze and empirical lens on the healing practices of Aeta women healers as well as the lessons, insights and perspectives which may have been previously missed; (b) my research attempts not to be 'neutral' but instead be an exercise in participatory action research and as such hopefully brings a new space of decolonization by documenting Aeta women healers’ contributions in the political and academic arena; and (c) it is an original contribution to postcolonial, anti-colonial and Indigenous feminist theories particularly through its demonstration the utility of these theories in understanding the health of Indigenous peoples and global health. There are 12 Aeta women healers who participated in the Talking Circle. This study is significant in grounding both the theory and the methodology while comparatively evaluating claims calibrated against the benchmark of the actual narratives of Aeta women healers. These evaluations subsequently categorized my findings into three themes: namely, identity, agency and representation. This work is also important in illustrating the Indigenous communities’ commonalities on resistance, accommodation, evolution and devolution of social institutions and leadership through empirical example. The work also sheds light on how the members of our Circle and their communities’ experiences with outsider intrusion and imposed changes intentionally structured to dominate them as Indigenous people altered our participants and their communities. Though the reactions of the Aeta were and are unique in this adaptive process they join a growing comparative scholarly discussion on how contexts for colonization were the same or different. This thesis therefore joins a growing comparative educational literature on the contextual variations among global experiences with colonization. This is important since Indigenous Peoples' experiences are almost always portrayed as unique or “exotic”. I can now understand through comparison that many of the processes from military to pedagogical impositions bore striking similarities across various colonial, geographical and cultural locations.
Aberrations in Cytokine Signaling in Leukemia: Variations in Phosphorylation and O-GlcNAcylation
Keywords: Chronic Lymphocytic Leukemia
Immunogenicity
Interferon (IFN)
Signal Transducer and Activator of Transcription (STAT) 1
STAT3
Reactive Oxygen Species (ROS)
Tumor suppressor p53
phosphatases
Toll-like receptor (TLR)-7 agonist
phorbol esters
immunosuppressive cytokines
O-GlcNAc
Hexosamine Biosynthetic Pathway (HBP)
Glucosamine
Resveratrol
Friend Erythroleukemia
RL2 antibody
cancer vaccines
IL-2
tumor immunosuppression
phosphorylation
O-GlcNAcylation
cytotoxic T lymphocytes (CTLs)
Ataxia telangiectasia mutated (ATM)
Antigen presenting cell (APC)
Immunotherapy
OGT
OGase
glucose
tumor metabolism
PKC
CD83
Warburg effect
tumor microenvironment
IL-10
tumor-reactive T cells

Tumor-induced immunosuppression can occur by multiple mechanisms, each posing a significant obstacle to immunotherapy. Evidence presented in this dissertation suggests that aberrant cytokine signaling, as a result of altered metabolism of Chronic Lymphocytic Leukemia (CLL) cells, confers a selective advantage for tumor survival and growth. Cells from CLL patients with aggressive disease (as indicated by high-risk cytogenetics) were found to exhibit prolongation in Interferon (IFN)-induced STAT3 phosphorylation, and increased levels of reactive oxygen species (ROS) in these cells reflected these signaling processes. Changes in the relative balance of phospho-STAT3 and phospho-STAT1 levels, in response to combinations of IL-2 + Toll-like receptor (TLR)-7 agonist + phorbol esters, as well as IFN, were associated with the immunosuppressive and immunogenic states of CLL cells. In addition, immunosuppressive leukemic cells were found to express high levels of proteins with O-linked N-acetylglucosamine (O-GlcNAc) modifications, due to increased metabolic activity through the Hexosamine Biosynthetic Pathway (HBP), which caused impaired intracellular signaling responses and affected disease progression. A conclusion of the studies presented here is that the intrinsic immunosuppressive properties of leukemic cells may be overcome by agents such as Resveratrol that target metabolic pathways of these cells.
New Directions in Metal Chalcogenide Nanochemistry
Keywords: Nanocrystals
Materials

Colloidal semiconductor nanocrystals have shown great promise in functional devices such as solar cells and LEDs, but still relatively little is understood about the chemistry of their formation and resulting structure. In this thesis, we describe the results of our study of ultrathin Bi2S3 nanowires, part of the emerging class of materials at the transition from molecular scale clusters to nanowires, from a chemical perspective. Using a complementary suite of techniques, we propose an atomically precise model of the nanowires accounting for both the inorganic core structure and ligand-surface interaction for purified dispersions. The growth process of the nanowires was studied using in situ NMR on reaction mixtures and information on the growth and reactivity not attainable with purified dispersions was gained. The small molecule reactivity of the sulfur-oleylamine precursor was elucidated and it was shown that H2S is produced in situ leading to the formation of Bi2S3. This knowledge allowed for the extension of the sulfur-oleylamine precursor to SemSn-oleylamine, which produces H2S and H2Se in situ leading to the formation of homogeneous solid-solution PbSxSe1-x nanocrystals with tunable stoichiometry. Through this work, we elucidated each stage of the nanowire formation from small molecule reactivity, to growth process, to solution phase structure.
Ventral Tegmental Area GABAA Receptors Mediate the Change from a Drug-naive to an Opiate- or Ethanol-deprived Motivational State
Keywords: motivation
morphine
ethanol
ventral tegmental area

A crucial question in drug addiction research concerns whether the varying reports of dopamine-independent and dopamine-dependent motivation can be integrated. According to one theory, the prior drug history of a subject — that is to say, whether they have received minimal or chronic drug exposure — determines whether opiate motivation is dependent upon the brainstem tegmental pedunculopontine nucleus (TPP) or dopamine neurotransmission. The biological analogue of this change is thought to be a switch in the signalling properties (from hyperpolarizing to depolarizing) of ventral tegmental area (VTA) gamma-aminobutyric acid subtype-A (GABAA) receptors. In this thesis, I demonstrate that the mechanisms underlying opiate motivation can be selected artificially by manipulating the signalling properties of VTA GABAA receptors, irrespective of the past drug history of the subject. Furthermore, I suggest that these same VTA GABAA receptors also play a similar role in controlling ethanol motivation. Indeed, the mechanisms underlying ethanol motivation can be doubly dissociated in a manner similar to that observed with opiates. However, whereas opiate motivation is TPP-dependent in the drug-naive state, I found that ethanol motivation was dependent on dopamine neurotransmission (via the D2 receptor) in drug-naive animals. Conversely, ethanol motivation was TPP-dependent in ethanol-deprived mice (as opposed to opiate motivation being dopamine-dependent in opiate-deprived animals). These effects are consistent with a VTA GABAA receptor switching mechanism identical to the one seen in the case of opiate motivation.
Grammatical Optionality and Variability in Bilingualism: How Spanish-English Bilinguals Limit Clitic-climbing
Keywords: language acquisition
Spanish-English bilingualism

This thesis considers how different groups of Spanish speakers (monolinguals, early bilinguals and late bilinguals) organize and limit grammatical optionality related to the placement of Spanish pronominal clitics with many complex infinitival constructions (Spanish clitic-climbing). In examining empirical work on the process and outcome of early and late dual language exposure and how early and late bilinguals acquire and limit grammatical optionality, this study will contribute to our understanding of 1) the nature of language-related cognition at different ages; 2) the systematic nature of bilingual language behaviour in child and adults (transfer, cross-language influence, etc.); 3) the cognitive and contextual factors associated with age of exposure to bilingualism to explain bilingual language behaviour; and 4) the importance of incorporating a clear model of language variation (language-internally and cross-linguistically) into a formal model of (bilingual) language. The empirical study conducted here tested how highly proficient heritage speakers (HS) of Spanish (native speakers of Spanish and Spanish-English bilinguals) deal with the optionality of clitic-climbing structures compared to monolingual speakers (native speakers) and highly proficient adult L2 speakers of Spanish (Spanish-English bilinguals). Forty participants completed a picture elicitation task testing a lexical limitation of the optionality, and an acceptability-preference task testing the speakers’ judgments on structural, semantic and lexical limitations of the optionality. Results show that all groups of speakers exhibited knowledge of syntactic constraints associated with pronominal placement in Spanish (optional clitic-climbing) infinitival sentences. All groups also performed similarly in exhibiting sensitivity to non-categorical factors that have been shown to guide the preferences of monolingual Spanish speakers. However, in the production task, the heritage speakers significantly outperformed the monolingual and non-native speakers of Spanish in their use of the Spanish-specific variant (proclisis). I explain these results through both cognitive and contextual factors related to age of exposure to bilingualism, and I discuss how the production results may underestimate a monolingual-bilingual difference for this optional domain.
Examining the Role of Endoplasmic Reticulum Stress in Pancreatic Beta-cell Biology
Keywords: endoplasmic reticulum stress
pancreatic beta-cell
unfolded protein response
ATF6
GRP78
type 2 diabetes

Pancreatic beta-cells are responsible for secreting insulin into the circulation to maintain whole body glucose homeostasis. While pancreatic beta-cells have a large capacity to secrete insulin, their function progressively deteriorates during the pathogenesis of type 2 diabetes as a result of both genetic predisposition and environmental factors. Obesity is the largest risk factor for developing type 2 diabetes and is associated with various conditions that can impair normal beta-cell function, including excess free fatty acids, inflammation and insulin resistance. Accumulating evidence in the literature suggests that endoplasmic reticulum (ER) stress contributes to the molecular mechanism of pancreatic beta-cell failure during the progression of type 2 diabetes. In this thesis, I have examined the role of the ER stress sensor ATF6-alpha and also the ER-resident chaperone GRP78 in pancreatic beta-cell homeostasis and function. Work presented in Chapter 2 examined the function of naturally occurring ATF6-alpha protein variants associated with type 2 diabetes. I also examined the role of endogenous ATF6-alpha in pancreatic beta-cells, which is described in Chapter 3. Results from these analyses suggest that the ATF6-alpha gene is not a type 2 diabetes susceptibility gene; however, ATF6-alpha protein expression is important to beta-cell function and survival. Finally, ER stress markers have been detected in pancreatic beta-cells and insulin sensitive tissues (such as adipose and liver), which promote beta-cell dysfunction and insulin resistance, respectively. In Chapter 4, I examined the contribution of ER stress in beta-cell dysfunction specifically by generating transgenic mice over-expressing GRP78. The mice were subsequently challenged by high fat diet to determine their susceptibility to developing symptoms of type 2 diabetes. Indeed increased chaperone capacity in pancreatic beta-cells protected against obesity-induced glucose intolerance and insulin resistance. Overall, these data support the hypothesis that ER stress contributes to beta-cell dysfunction in type 2 diabetes progression.