VictorJuiz/thesis huggingface dataset:
The Effect of Important Food Sources of Fructose-containing Sugars on Adiposity: A Systematic Review and Meta-analysis

Sugar-sweetened beverages (SSBs) are associated with increased weight gain. It remains unclear if other food sources of fructose-containing sugars show a similar relationship. We conducted a systematic review and meta-analysis of controlled trials to assess the effect of different food sources on body weight (primary outcome) and other adiposity measures. We identified 119 controlled trials (368 trial comparisons, N=5,263). Total fructose-containing sugars increased body weight (MD, 0.29kg [95% CI, 0.05 to 0.53]; moderate-certainty evidence) and body fat (MD, 0.0.47% [95% CI, 0.09 to 0.85]; low-certainty evidence) in addition trials (energy from sugars added to diet) with no effect in substitution (energy matched comparisons), subtraction (energy from sugars subtracted from diet), or ad libitum trials. There was evidence of interaction by food source with SSBs and mixed sources increasing body weight in addition trials. Energy control and food source appear to be mediators of the effect of fructose-containing sugars on adiposity.

Keywords: Food sources of sugars
Fruit
Obesity
SSB
Systematic Review and Meta-analysis
Weight gain
Advisor: Sievenpiper, John
Establishing Zebrafish Embryonic Axial Curvature as a Scoliosis Surrogate Model to Screen for Pathogenic Mechanisms and Therapeutic Strategies

Idiopathic scoliosis (IS) is characterized by abnormal spinal curvatures arising without observable vertebral or physiological anomalies. Genetic heterogeneity and historical lack of relevant animal models have hindered understanding of mechanisms driving disease. Consequently, scoliosis treatments rely on invasive mechanical spinal corrections. Our lab first demonstrated that zebrafish faithfully recapitulate hallmarks of human IS. We identified disruptions in cerebrospinal fluid flow/homeostasis and neuroinflammation as drivers of zebrafish IS, and found that pharmaceutical immunomodulation suppresses spinal curvature. As scoliosis develops and progresses slowly, an embryonic phenotype linked to scoliosis would facilitate small molecule suppressor screening for mechanisms underlying spinal curvature, while revealing targets amenable to therapy development. Herein I establish zebrafish embryonic ventral tail curvature as a functional scoliosis surrogate model. In exploiting this discovery, I identified novel chemical therapy in a new zebrafish model of IS and implemented a high-throughput embryonic screening platform providing potentially translatable biology and therapeutic targets.

Keywords: chemical screening
idiopathic scoliosis
neuroinflammation
oxidative stress
therapy discovery
zebrafish
Advisor: Ciruna, Brian G
A Deep Learning-based Cyberattack Detection and Mitigation System for Transmission Protective Relays

There is a pressing need for the development of cyberattack detection and mitigation systems for substations and in particular protective relays, a critical component of substation operation. Multiple false transmission line trippings initiated by coordinated cyberattacks on protective relays can cause large scale power disturbances and cascading failures. This thesis presents a deep learning-based cyberattack detection and mitigation system (CDMS) for transmission line protective relays. The proposed CDMS consists of a convolutional autoencoder based anomaly detector that is first trained with power measurements representing various types of fault and fault-free conditions. The CDMS is then employed to detect measurements that are maliciously injected by an attacker. The proposed CDMS is evaluated under a variety of cyberattack scenarios and is capable of blocking most attacks without interfering with normal relay operations. This thesis also evaluates the security and robustness of the machine learning model within the CDMS under a white-box attack.

Keywords: Anomaly Detection
Cyberattack Detection Systems
Cyberphysical Systems
Deep Learning
Operational Technology
Transmission Protective Relays
Advisor: Kundur, Deepa
Spatial Variation of Circadian Gene Expression in the Rodent Brain

The brain plays a major role in the coordination of circadian rhythms in the body. However, it has been demonstrated that circadian transcriptome oscillations in the bulk brain exhibit dampened amplitude compared to peripheral organs. This paradoxical phenomenon can be explained by the complexity of anatomical structures within the brain which may exhibit phase differences in the expression of circadian genes. To address this question, we investigated Per2 and Arntl expression during the circadian cycle in thousands of isometric voxels in the rat brain. We identified a previously uncharacterized spatiotemporal organization of circadian rhythms in the brain. The acrophase time of Per2 and Arntl expression is incrementally delayed with increasing distance from a caudomedial region of the brain. Our results confirm circadian heterogeneity of the brain and point at a new mechanism of phase regulation across brain regions.

Keywords: Brain
Circadian rhythm
Melatonin
Advisor: Petronis, Arturas
The Role of PAK Signaling in Social Memory

Long-term memory is retained in cells which retain structural changes induced by repeated stimulation, termed engram cells. The p21-activated kinase (PAK) signaling pathway is known to be important in the regulation of synaptic structures and subsequent plasticity, but its role in engram cells is unknown. In this project, I used a tetracycline inducible system to express mutant PAK3 proteins, which inactivates the PAK pathway, to address this question. Mutant PAK3 proteins were expressed mostly in excitatory neurons of the cortex, hippocampus, and amygdala and led to reversible social memory deficits in mutant mice. Social memory engram cells were weakly labelled in the hippocampus. Acute optogenetic inhibition of excitatory cells in the entorhinal cortex perforant pathway led to similar social memory deficits in control animals, but may reduce deficits in mutant animals. These findings contribute to the understanding of social memory engram cells and the role of PAK in social discrimination.

Advisor: Jia, Zhengping
TMI on TBI: Multi-approach Proteomics Discovery of Traumatic Brain Injury Biomarkers

Traumatic brain injury (TBI) has recently been highlighted as a significant public health concern, affecting over 65 million patients worldwide per year. Despite increased awareness, reliable diagnostic and prognostic biomarkers are urgently needed to improve patient care. Here, we use mixed proteomics approaches - including high-throughput multiplex immunoassay and mass spectrometry - to identify brain injury biomarkers in the serum and cerebral spinal fluid (CSF) of severe TBI (sTBI) patients. We identify a candidate list of diagnostic markers that are perturbed in sTBI patients in comparison with non-brain injury controls, with significant ability to discriminate the presence of TBI. In addition, we discover candidate prognostic markers that are significantly correlated to clinical indicators of TBI and are able to predict survival outcome in sTBI patients. The preliminary findings presented in this pilot study represent a promising starting point for future validation, where candidate biomarkers can be tested in independent TBI cohorts.

Advisor: Diamandis, Eleftherios
A Novel Memory Paradigm to Examine Behavioural Pattern Completion and Pattern Separation

Pattern completion and pattern separation are distinct computational mechanisms that support episodic memory. Human studies manipulate image completeness to index behavioural pattern completion (BPC). Study-test image similarity is manipulated for behavioural pattern separation (BPS), which is assessed in the Mnemonic Similarity Task (MST). The MST, however, does not directly index BPC, and rather attributes generalization of similar items (lures) as previously studied to BPC. The goal of the current study was to modify the MST to directly assess BPC (by varying image completeness at test) and BPS (by varying image similarity at test) in one session. Participants (n=51) made ‘old’/‘new’ judgements to distinguish among studied and novel images. Results showed a positive correlation between BPS and BPC and no correlation between lure generalization and BPC. Our findings indicate that BPS and BPC may share underlying neural mechanisms. Contrary to previous interpretations of MST performance, these results suggest that lure generalization and BPC are independent.

Keywords: episodic memory
humans
pattern completion
pattern separation
Advisor: Olsen, Rosanna K.
Buchsbaum, Bradley R.
Prefrontal Cortical Thickness and Hippocampal Volume Maintained in Women Taking E2 Replacement Therapy Post Bilateral Salpingo-oophorectomy

Bilateral oophorectomy prior to spontaneous menopause is associated with increased risk of dementia. A likely mechanism behind this increased risk is the sudden drop in 17β-estradiol (E2) which occurs following surgery. The current study examines whether E2 replacement therapy in women who have a bilateral salpingo-oophorectomy (BSO) maintains verbal and working memory performance, prefrontal cortical thickness and hippocampal volume. Women were tested before and after BSO. Overall results indicate a beneficial effect of E2 on cognitive performance and brain structure following BSO, as no changes are observed between the pre- and post- testing sessions. However, examination of pre- and post-BSO outcomes for individual women reveals that E2 replacement is not universally beneficial in maintaining verbal memory performance and prefrontal structure. These findings have implications for clinical practice as, while they provide evidence in support of the use of E2 for many surgically menopausal women, they also explore limitations of E2 effectiveness.

Advisor: Einstein, Gillian
Investigation of the Immunologic Changes that Discriminate Asymptomatic Antinuclear Antibody Positive Individuals from Systemic Autoimmune Rheumatic Disease Patients

The Systemic Autoimmune Rheumatic Diseases (SARD) are a class of chronic autoimmune diseases with widespread inflammation leading to heterogenous clinical manifestations and significant morbidity. Antinuclear antibodies (ANA) are the hallmark of SARD but are also detected in healthy individuals. Some immune abnormalities associated with SARD have also been identified in asymptomatic ANA+ individuals. Here, we demonstrate that asymptomatic ANA+ individuals have significant immune activation as compared to ANA- healthy controls, which is intensified in individuals who will progress to SARD. Furthermore, elevated monocyte levels and trends to decreased regulatory T cells were observed in SARD patients compared to asymptomatic ANA+ individuals indicating that the balance of proinflammatory to regulatory factors is central to SARD progression. These findings enhance our understanding of the immune mechanisms involved in SARD pathogenesis and suggests that ANA+ individuals with the highest immune activation have an increased risk of progression.

Keywords: Antinuclear Antibody
Autoimmune
Advisor: Wither, Joan
Investigating the Molecular Role of Tubby in Subcellular Localization of RNAs

Mice and humans deficient in the Tubby (Tub) protein, which contains a nucleic acid-binding TUB domain, exhibit maturity-onset obesity, insulin resistance, and sensorineural deficits. We found that Tub has roles in RNA localization. As seen for many RNA binding proteins governing subcellular mRNA localization, I demonstrated that nuclear localization of Tub is essential for its regulation of localization of its target Neuropeptide Y and that Tub-bound sequences can repress translation. To investigate the shared roles of Tub and the related Tulp3 in ciliary trafficking, I showed that disruption of the phosphoinositide PI(4,5)P2 binding motif did not affect their ciliary localization, and induced nuclear localization of Tub but surprisingly not Tulp3. Using the MS2 RNA binding system, I have taken the first steps to examine Tub-dependent ciliary GPCR RNA localization. Altogether, I provide evidence that begins to explore the RNA-based mechanism of Tub in regulating subcellular mRNA localization.

Keywords: RNA localization
Tubby
Tulp3
Advisor: Cordes, Sabine P
Seasonality and the Immune System during Pregnancy: Impact of Seasonal Affective Disorder

The current analysis examined whether high maternal seasonality was associated with a unique pattern of immune activity during pregnancy. Plasma C-reactive protein (CRP) was measured in 100 highly seasonal mothers and 100 matched controls in the 1st and 3rd trimester. In trimester 1, highly seasonal women had significantly lower CRP than controls. There was no effect of season on CRP for both study groups during pregnancy. In a subsample, gene expression of pro- (IL1β, IL6, TNFα) and anti-inflammatory (IL4, IL10) cytokines were measured in peripheral leukocytes. No cytokine gene expression differences between groups were detected. Multiple regressions were conducted to predict CRP using BMI, maternal seasonality group, gene expression of each cytokine, and cytokine by seasonality group interaction. Significant predictor variables were IL1β by group interaction and IL10 gene expression. These findings suggest highly seasonal pregnant women have a different immune profile than control women in early gestation.

Keywords: Inflammation
Pregnancy
Seasonal Affective Disorder
Seasonality
Advisor: Levitan, Robert
Matthews, Stephen
Characterization of the Role of Downstream Regulatory Element Antagonist Modulator (DREAM) in the Murine Circadian Clock

DREAM is a multifunctional Ca2+ binding protein with diverse functions both inside and outside the nucleus. However, no study to date has examined the role of DREAM within the suprachiasmatic nucleus (SCN), even though DREAM is present in high abundance in the SCN. Here, we find that DREAM ablation results in a shorter period of wheel-running activity and impaired entrainment to environmental light cycles. However, at the molecular level, the absence of DREAM established no significant change in the expression of pERK, immediate early genes and clock genes. At the transcriptome level, RNA-seq analysis suggests that DREAM may be involved in or impact cellular stress mechanisms, cell excitability, and structural remodelling of neurons. These findings identify DREAM as a potential regulator of circadian clock speed and photic entrainment. However, further experiments are needed to find the precise role and mechanism of action of DREAM within the SCN.

Keywords: Calcium binding protein
Calcium Signaling
Circadian rhythm
Light Entrainment
Suprachiasmatic Nucleus
Transcription Repressor
Advisor: Cheng, Mary
Information Effects on Parental Preferences for Regulatory Types of Early Childhood Education and Care

Choosing early childhood education and care (ECEC) services is a complex process and research has shown that parents are poorly informed consumers of these services. Experimental studies show that when participants are informed on the importance of a specific decision, they engage in a more complex decision-making process. In this paper, we test whether providing parents with information about the regulatory stringency of ECEC options available to them would influence their ECEC preferences. A conjoint survey capturing quasi-behavioural preferences of ECEC services was completed by 682 parents. Prior to engaging with the survey, participants were randomly assigned to a treatment that informs them about the stringency of oversight of ECEC options available in the province of Ontario or a control group. Receiving information did not meaningfully change the preferences of the entire sample. However, subgroup analysis of parents identified as lower-resourced indicates an important information effect for parent decisions.

Keywords: Conjoint Analysis
ECEC
Information Effects
Parental Preferences
Advisor: Perlman, Michal
White, Linda
Physical and Mechanical Properties of a Dental Resin Covalently Attached to Epigallocatechin-3-gallate

Background: Epigallocatechin-3-gallate (EGCG) is an antibacterial green tea polyphenol that can inhibit dentinal protease activity and help preserve dentin-bond strength. However, current methods of EGCG delivery involve passive inclusion of EGCG into methacrylates, leading todiffusion of EGCG and rapid depletion of its bioactive properties. Objectives: To evaluate the physico-mechanical properties of a novel resin based on methacrylate copolymer covalently attached with EGCG. Methods: Resins were formulated with EGCG functionalized at varying degrees (E33, E67, and E100) and varying concentrations (0.5, 1, 2, 5, 10%), and compared to passively incorporated EGCG (E0) and the control group (TEGDMA). Degree of conversion (n=3), flexural strength, modulus of elasticity, modulus of resilience, and microhardness were tested (n=8). Results: EGCG-methacrylate groups had statistically similar physico-mechanical properties to control group except 10% E33. Conclusions: Functionalized EGCG-methacrylate groups except 10% E33 possess adequate physico-mechanical characteristics to progress with further testing in an innate dentin matrix model.

Keywords: EGCG
epigallocatechin-3-gallate
green tea
mechanical properties
Advisor: Prakki, Anuradha
Deciphering the Molecular Actions of Suppressor of Fused in Hedgehog Signaling and Sonic Hedgehog Medulloblastoma

Suppressor of Fused (SUFU) is a key regulator of the Hedgehog (Hh) pathway and is implicated in a subset of Sonic Hedgehog medulloblastoma (SHH MB). Although extensively studied, characterization of the molecular actions and protein interactions of SUFU in SHH MB are still limited. My project focused on further elucidating the SUFU interactome and its molecular actions in Hh signaling and SHH MB. I performed pilot proteomic-based experiments to explore the SUFU interactome in a SHH MB context under near physiological conditions. I also prepared CRISPR reagents to generate Halo/HalomAID-tagged Sufu mouse lines and showed that these tags do not appear to affect the negative regulatory function of SUFU in vitro. Together, my project provides useful reagents that will allow our lab to study the physiological SUFU interactome and for the generation of useful mouse models to elucidate the molecular actions of SUFU in Hh signaling and SHH MB.

Keywords: Hedgehog signaling
Medulloblastoma
Sufu
Advisor: Hui, Chi-chung
Investigating Sialic Acid Deficiency on Promoting Renal Thrombosis

Atypical Hemolytic Uremic Syndrome (aHUS) is a rare condition which causes thrombosis in the renal microvasculature. Pneumococcal aHUS (P-aHUS) is a rare subtype resulting from severe Streptococcus pneumoniae infections. Although the pathophysiology of P-aHUS remains unknown, patients often present with high blood levels of sialidase, enzymes which remove terminal sialic acids from cell surface glycans. Recently, recessive mutations resulting in loss-of-function in the sialyltransferase ST3GAL1 were identified in three siblings with aHUS. To determine how sialic acid-deficiency promotes thrombosis in the renal microvasculature, the desialylated glycoproteins expressed on sialic acid-deficient endothelial cells were identified and the renal phenotypes of sialic acid-deficient rats were characterized. In total, 5 desialylated glycoproteins of interest were identified by mass spectrometry proteomics, while sialic acid-deficient rats were revealed to have significant renal microvasculature injury. The data collected provides evidence for sialic acid-deficiency as a mechanism for promoting renal thrombosis, and potentially novel targets for future study.

Keywords: Endothelial
Glomerulus
Glycan
Kidney
Platelet
Sialic Acid
Advisor: Lemaire, Mathieu
Functional Characterization of Proximity-dependent Degraders

Over the past two decades, research efforts have aimed to develop event-based therapeutics for targeted protein degradation (TPDs). In recent years, TPDs were developed to hijack E3 ligases for the targeted degradation of proteins of interest. E3 ligases are components of the ubiquitin proteasome system that determine the target specificity of ubiquitylation reactions. The development of novel TPDs is currently limited by a reliance on a few E3 ligases. I established a large-scale forced-proximity screen for identifying potent degraders. I identified UBE2B as a highly potent degrader that outperformed E3 ligases currently recruited by TDPs, suggesting it as a prime candidate for TPD development. Analysis of uncharacterized protein PRR20A suggested wider screen versatility with putative identification of a degron sequence capable of protein degradation both in cis and in trans. Together, my results suggest my novel screening platform can facilitate functional characterization of mammalian quality control and degradation systems and identify novel candidates for TPD development.

Keywords: E3 Ligase
FACS-Based Screening
ORFeome
Targeted-Degradation Therapeutics
Ubiquitin Proteasome System
Advisor: Taipale, Mikko
Salvianolic Acid B Inhibits Platelet Aggregation and Blood Coagulation

Dan Shen extracts have been reported for centuries to control cardiovascular diseases in Chinese medicine, and its depside salts are approved in China to treat chronic angina. As the most abundant active compound of Dan Shen, salvianolic acid B (SAB) has been shown to exhibit anti-thrombotic properties in animal models. However, its mechanism of action has not been adequately explored. Interestingly, we found SAB bears structural similarities to dabigatran. SAB reduced clot weight, delayed coagulation determined by PT, aPTT, and TEG. Confocal and scanning electron microscopy revealed SAB also reduced fibrin network density. We demonstrated SAB attenuates ADP- and collagen-induced platelet aggregation. Remarkably, SAB inhibits thrombin-induced platelet aggregation more potently than other agonists. Ex vivo perfusion chamber studies showed SAB reduced platelet adhesion/aggregation under flow conditions. These data establish a novel mechanism of SAB in the inhibition of platelet aggregation and blood coagulation, likely partially through direct thrombin inhibition.

Keywords: Cardiovascular Disease
Coagulation
Hemostasis
Platelet
Thrombin
Thrombosis
Advisor: Ni, Heyu
A Molecular-level Investigation of Soil Organic Matter Responses to Climate Change in Two Temperate Forests

Climate change is expected to alter the amount and type of carbon (C) stored in forests as soil organic matter (SOM). To better understand the response of forest SOM to warmer temperatures and enhanced nitrogen (N) deposition, samples were collected from the Detrital Input and Removal Treatment plots at University of Michigan Biological Station and the Soil Warming and Nitrogen experimental plots at Harvard Forest after 10 years of manipulation. Molecular-level analytical techniques were used to understand the composition and degradation state of SOM from these plots. Results indicated that although neither site showed changes in the amount of C or N stored after 10 years, there were changes in the composition and decomposition state of SOM. The results of this thesis have demonstrated that forest SOM cycling and storage are sensitive to environmental change, and also highlight the importance of long-term forest manipulation studies.

Keywords: cutin
lignin
nuclear magnetic resonance spectroscopy
organic matter biomarkers
soil organic matter
suberin
Advisor: Simpson, Myrna J