VictorJuiz/thesis huggingface dataset:
Application of a Novel Di-substituted 1,4-Benzodiazepine 2,5-Dione Library for the Stabilization of p53 Through Inhibition of HDM2
Keywords: benzodiazepine
HDM2
p53

The HDM2 protein plays a critical role in the inhibition and degradation of p53, a key mediator of cell cycle arrest and apoptosis. The inactivation of p53 is known to be oncogenic, therefore the inhibition of HDM2 promotes apoptosis in cancer cells. In this study we describe a second round of structural activity relationship optimization on a directed library of 1,4-benzodiazepine 2,5-dione inhibitors of HDM2 for the treatment of acute myeloid leukemia. First the rational and synthetic route of the library is described. The cytotoxicity of library members is then assessed in several cell lines in the effort to establish selective activity in p53 wild type cancer cells. The biological activity of the lead compound was then evaluated by Western blot analysis for biomarkers of the induction of p53 activity.
Development of a New Mulitcomponent-Multicatalytic Reaction of Vinyl Pyrazine Utilizing Orthogonally Reacting Boron Coupling Reagents
Keywords: Dual Metal Catalysis
Multicomponent
Organoboron
Palladium
Rhodium

Multicomponent-Multicatalyst Reactions (MC)2R, which utilize multiple metal catalysts to form multiple bonds under a single set of reaction conditions, are an emerging area of research in the Lautens group. They represent a method for rapidly generating complexity and increase time and cost efficiency due to the elimination of isolation and purification of intermediates. Building on previous work from our group, a new strategy of (MC)2R using vinyl pyrazine has been developed. This new strategy merges the Hayashi-Miyaura reaction with a base-mediated SNAr and a Suzuki coupling in a one pot-one step process forming three new bonds under a single set of reaction conditions. The robustness of the process has been shown through the synthesis of a compact library of compounds (18 examples, 52-88% Yield). The key feature of this strategy is the utilization of an unprecedented pair of orthogonally reacting boron coupling reagents which allows for the excellent selectivity and yields observed.
Differences Between Domestically Violent and Non-violent Fathers' Perception of their Children in a Three Minute Interview
Keywords: Abuse
Domestic Violence
Fathering
Maltreatment
Reflective Functioning
Trauma

The present study examined the differences between domestically violent and non-violent fathers' brief perceptions of their child. Based on prior research on male batterers, a coding scheme was developed to assess fathers' ability to perceive their child. It was hypothesized that domestically violent fathers would make more self-referential comments in relationship to their child after accounting for potential confounding sociodemographic factors. The sample included 85 fathers; 40 who had domestic violence charges, and 45 with no self-reported history of perpetrating domestic violence. Children, about whom fathers reported, ranged in age from 3 to 16 years. Results indicated that domestically violent fathers made more self-referential comments, consistent with clinical descriptions of male batterers. These findings suggest there is a parenting deficit in perceiving the child as an intentional being, and the mechanisms of father maltreatment may differ. Contributions of other variables, such as father's age and child contact, are discussed.
Design and Evaluation of an Evaporator for a 1 kW Organic Rankine Cycle System
Keywords: cogeneration
efficiency
energy
organic
rankine

A 1 kW organic Rankine cycle (ORC) was designed, produced and evaluated. The system used an organic working fluid to generate power from a low temperature heat source. Considering both safety and performance, R-245fa was selected as the optimum organic fluid for the application. The necessary evaporator coil sizing was calculated and a standard air handler burner was modified to provide a heat source. An exhaust gas dilution system was developed to reduce the evaporator heat transfer temperature and protect the working fluid from thermal decomposition. A kinematically rigid scroll expander produced 334 W of electrical power, while the ORC system achieved a cycle efficiency of 1.9%. It is hypothesized that the reduced power output was due mainly to pump delivery issues leading to an instable refrigerant mass flow rate. Moreover, the pump did not provide the desired amount of pressure head, resulting in off-design operating conditions throughout the cycle.
Understanding Maltreatment: A Secondary Analysis of the 2008 Canadian Incidence Study of Reported Child Abuse and Neglect
Keywords: Abuse
Children
Fathers
Maltreatment
Perpetrators
Risk Factors

Little work to date has been done to understand perpetrators of maltreatment within Canadian families. This is especially true for biological fathers and stepfathers. The current study utilized data from the 2008 Canadian Incidence Study of Reported Child Abuse and Neglect to determine perpetration patterns in two parent, single caregiver, and blended family households. The study also examined risk factors associated with maltreatment. Results suggest that parents come to the attention of child welfare services for different reasons; fathers tend to be investigated for exposing children to domestic violence and mothers for physical abuse. While mothers were identified as perpetrators of neglect more often than fathers, the majority of neglect investigations involved both parents as co-perpetrators. Mothers and fathers showed different risk profiles. Specifically, fathers were more likely to abuse substances but less likely to have mental health issues or poor social support. Implications for policy and practice are discussed.
Study on the Phagocytosis of Asbestos Fibers and the Mechanisms for its Frustrated Phagocytosis in Macrophages
Keywords: Asbestos
Fibers
Macrophage
Phagocytosis

Asbestos is a group of mineral silicates with fibrous morphology, which cause various respiratory diseases, including mesothelioma. Fiber toxicology has evolved a paradigm to explain the toxicity of asbestos fibers. It states that fibers >15 um cannot be completely engulfed by alveolar macrophages, thereby aborting phagocytosis in a process called frustrated phagocytosis. To study the mechanisms that cause this phenomenon, we investigated the phagocytosis of asbestos by confocal microscopy in cultured murine and human macrophages. Our findings showed unexpected differences in asbestos phagocytosis between murine and human cells. While murine macrophages completely engulfed fibers >15 um, albeit through a process that deviated from the canonical phagocytic pathway, phagocytosis arrested at the phagocytic cup stage in human macrophages. Strikingly, we restored phagocytosis in human macrophages by indirectly opsonizing fibers, which directed their uptake via Fcy-receptors. Altogether our results indicate that phagocytic receptors for asbestos determine its frustrated phagocytosis.
Regulation of Argonaute Proteins and Small RNA Pathways in Caenorhabditis elegans by CHORD Domain Protein-1 (CHP-1)
Keywords: Argonaute
C. elegans
CHORD domain protein
DAF-21
Hsp90 co-chaperone
Small RNA

Caenorhabditis elegans CHP-1 (CHORD-domain containing protein 1) has been shown to be required for embryogenesis and germline development. I observed that CHP-1 interacts with certain Argonaute (AGO) proteins and may play a role in related small RNA pathways. Recent research suggests Hsp90 and co-chaperones may regulate small RNA pathways; CHP-1 homologues have also been identified as Hsp90 co-chaperones. There has yet to be a mechanism identified for how chaperone proteins and CHP-1 may function to regulate AGO function in C. elegans. In this thesis, I will provide evidence of an interaction between CHP-1 and the C. elegans Hsp90 homologue DAF-21, as well as the existence of a CHP-1/DAF-21/AGO complex. Additionally, I will show that loss of CHP-1 has differential effects on AGOs and small RNAs across multiple small RNA pathways. Together, these studies constitute the first report of chaperone-mediated regulation of small RNA pathways in C. elegans.
Maternal and Infant Variables Associated with Critical Volumes of Breastmilk in Very Low Birth Weight Infants During the First Month of Postnatal Life
Keywords: breastfeeding
breastmilk
preterm infants
very low birth weight

This study investigated the variables associated with the initiation, duration and exclusivity of breastmilk feeding in very low birth weight (VLBW) infants. Maternal and infant correlates associated with the provision of a critical dose, ¡Ý50 ml/kg/d, of mother¡¯s own milk in the first 28 days of life was also determined. Data including socio-demographic and health characteristics were collected prospectively for 115 mothers and infants. Ninety-six percent of infants received some mother¡¯s milk during hospitalization. Sixty-eight percent of infants received some breastmilk at discharge and 48% fed exclusively mother¡¯s own milk. Maternal Asian background (p=0.005), birth weight ¡Ý1000 g (p=0.008), gestational age ¡Ý28 weeks at birth (p=0.01), and SNAP-II Score
Characterization of the Dependence of Src:ND2 Binding on Phosphorylation and Intramolecular Src Interactions
Keywords: intrinsically disordered protein
ND2
NMDAR
Src
tyrosine kinase

The role of the nonreceptor tyrosine kinase Src in up-regulating NMDAR activity via phosphorylating the carboxyl-terminal domain of NMDAR is well-known. The interaction between the intrinsically disordered regions of Src and an anchoring protein, ND2, is known to be essential in this up-regulation. However, the molecular mechanism underlying this docking remains elusive. We have demonstrated that the Src:ND2 interaction is phosphorylation regulated, resulting in an enhancement from no detectable binding to sub-micromolar binding, especially with Thr37/Ser75 phosphorylated. Moreover, we have discovered that the presence of SH3 domain increases binding affinity significantly from sub-millimolar to sub-micromolar. These results indicate how electrostatic interactions and intramolecular Src interactions influence the Src:ND2 interaction. Our findings expand knowledge of the regulatory possibilities of disordered proteins in general, and will be valuable for the development of therapeutic agents that target the Src:ND2 complex to treat the patients suffering from chronic pain.
Identification and characterization of adhesive proteins in freshwater mussels towards the development of novel bioadhesives
Keywords: bioadhesion
byssus
DOPA
mussel adhesive proteins

The European freshwater mollusk Dreissena bugensis (quagga mussel) adheres to a variety of underwater surfaces via the byssus, a proteinaceous “anchor”, from which threads are secreted. The threads terminate in small, disc-shaped adhesive plaques which have adapted to turbulent conditions with remarkable adhesive strength for their size. Top adhesive candidates that demonstrated evidence for an adhesive role were identified via LC-MS/MS and relative quantification of proteins between the mussel plaque and adhesive interface. For the first time, a top candidate for adhesive activity (Dbfp7) was isolated directly from the quagga mussel. We aim to incorporate relevant protein motifs from these proteins into peptide mimics and to recombinantly express Dbfp7, leading to the development of novel bioadhesives for medical and dental applications. Understanding the molecular mechanisms and proteins responsible for adhesion in freshwater mussels will provide a paradigm for medical adhesives which function reliably on wet tissue surfaces with minimal inflammation.
The effect of bisphenol A on pro-opiomelanocortin and circadian clock gene expression in POMC-expressing hypothalamic neuronal models
Keywords: Cell biology
Endocrine-disrupting chemical
Feeding-regulation
Metabolism
Neuronal cell lines
Neuropeptide

Bisphenol A (BPA) has been linked to obesity. However, the direct effect of BPA on hypothalamic pro-opiomelanocortin (POMC) neurons, which regulate energy homeostasis, remains unexplored. We describe here the effect of BPA on immortalized POMC-expressing cell models, mHypoA-POMC/GFP-2 and mHypoE-43/5. BPA increased the mRNA levels of Pomc at 1 and 4 hours. BPA altered the expression of Bmal1, Per2 and Rev-Erba circadian clock genes. BPA increased the expression of inflammatory markers Nfkb, Il6 and Ikba, and steroid receptors Esrrg and Pparg. BPA decreased the expression of steroid receptors Esr2 and Gpr30. Pre-treatment with GnRH, PS1145, and T0070907 abrogated BPA-mediated Pomc induction. BPA increased Pomc mRNA levels in the mHypoA-Bmal1KO cell line. BPA treatment for 20 minutes increased relative aMSH secretion. Bisphenol S did not alter Pomc expression. In conclusion, BPA may have direct effects on hypothalamic POMC neurons, with implications for understanding the role of BPA in the arcuate nucleus.
Design of a Polymer Transducing Pad as a Replacement for Commercial Ultrasound Gel in Low-Income Countries and Resource-Scarce Settings
Keywords: absorbent polymer
couplant
hydrogel
ultrasound imaging

A polymer pad has been formulated and tested to act as a conductive element between an ultrasound transducer and the human body during external ultrasound examinations. This pad acts as a replacement for commercially-available ultrasound gel, which is often difficult to acquire in low-income, resource-scarce, geographically inaccessible, and conflict areas, in addition to any type of zone with disrupted distribution channels for medical equipment. As ultrasound examinations are safe, portable, and relatively affordable, they are an important diagnostic imaging tool; a lack of ultrasound gel hinders the use of this technology. This polymer pad replaces the need for commercial ultrasound gel. It is composed of 4 chemical component groups: a divinyl backbone, acrylic acid and acrylate monomers, and an oligomeric poly(ethylene glycol). Certain formulations of this polymer pad can be used to produce ultrasound images that are comparable to those acquired using ultrasound gel and suggest prolonged reusability.
The Role of Acid Sphingomyelinase in Murine Placental Development
Keywords: acid sphingomyelinase
autophagy
fetal growth restriction
placenta
sphingolipids

Sphingolipids are a diverse class of bioactive signaling lipids that control an array of fundamental cellular processes. Recently, dysregulation of sphingolipid metabolism has been observed in placentas from complicated pregnancies. In the present study, we demonstrate that acid sphingomyelinase (Smpd1), an enzyme involved in sphingolipid metabolism, is critical for normal placental development, and that its deficiency results in fetal/intrauterine growth restriction (IUGR). Smpd1-/- placentas display several structural abnormalities, including a reduced labyrinth compartment and increased thickness of the fetal-maternal interhemal membrane. In addition, Smpd1-/- placentas exhibit a three-fold decrease in sphingosine-1-phosphate (S1P), a sphingolipid important for promoting angiogenesis. Finally, we observed several hallmarks of defective autophagy and lysosomal impairment in Smpd1-/- placentas, which could contribute to the IUGR phenotype. This study proposes Smpd1-deficient mice as a novel model of IUGR, and can aid in the understanding of molecular events which lead to IUGR and placental pathologies in humans.
Sustained Regional Anesthesia for Post-operative Pain Management
Keywords: Drug delivery
HAMC
Hydrogel
Local anesthetic
Pain
Sustained release

Acute post-operative pain is inevitable, yet current treatment strategies do not provide sufficient pain relief. While local anesthetics are widely used to achieve a regional block, they are currently delivered as a bolus liquid injection and, thus, quickly clear the injection site. Subsequently, pain relief is short-lived, and quick distribution of the drug throughout the body leads to systemic side effects. Post-operative pain management can be improved by a local, controlled and sustained drug delivery system that increases the duration of local anesthetic efficacy while minimizing side effects. Herein, a hyaluronan-methylcellulose hydrogel (HAMC) was investigated as a drug delivery vehicle to locally deliver pain medication over an extended period. By distributing particulates of a local anesthetic within HAMC, the hydrogel serves as a local drug depot and prevents fast clearance of the drug. The anesthetic-loaded HAMC system was optimized in vitro and then evaluated in rat models of nerve block.
Dynamic Modeling of Occupant Response to Frontal/Rear/Lateral Vehicular Collisions
Keywords: Biomechanics
Cervical injury
Collision
Dynamics
Finite element
Whiplash

Cervical injury is one of the primary concerns in vehicle collisions. In this work, two multibody dynamics models of the cervical spine of a 50th percentile male were developed using biofidelic variable intervertebral rotational stiffnesses. Furthermore, finite element simulations of a seated and restrained occupant in frontal, rear, and lateral collisions between two passenger cars were performed to determine the kinematics and kinetics response of the occupant. The resultant accelerations of the T1 vertebra were applied to the multibody dynamics models to obtain their true kinematic response. The multibody dynamics models and finite element models were used to estimate the risks of cervical injuries. Ligament injury was most likely at the interspinous ligament in frontal collision, the anterior longitudinal ligament in rear collision, and the near-side capsular ligament in lateral collision. The highest vertebral fracture risks were found in rear and lateral injuries, in the mid- and lower cervical spine.
Astroglial Plasticity within the Rat Orofacial Primary Motor Cortex Induced by Endodontic Treatment versus Tooth Extraction
Keywords: CLARITY
Dental injury
Glia
Motor cortex
Neuroplasticity
Rats

Objective: To optimise the CLARITY technique that renders brain tissue optically transparent, immunolabelling and light-sheet microscopy for 3D-characterisation of astroglial cytoarchitecture and morphology within the orofacial primary motor cortex of rats receiving endodontic versus tooth extraction treatment. Methods: Rats received either extraction, endodontic-, sham- or no-treatment of the right maxillary molar teeth. After one week, 2 mm-thick brain sections of the orofacial primary motor cortex were cleared and immunolabelled with astroglial markers. 3D-images were acquired with light-sheet microscope and Imaris software was used to characterise and quantify cytoarchitecture and morphological features of astroglial processes. Results: As compared with endodontic-, sham- and no-treatment, tooth extraction produced significantly thinner and straighter astroglial processes within layer-I of a laminar motor cortex. Conclusion/significance: Tooth extraction but not endodontic treatment induces astroglial plasticity within the rat primary motor cortex that controls orofacial motor functions. Astroglia may be a therapeutic target for preventing/curing postoperative motor impairments.
Children's Comprehension of Implicit Messages to Interpret Ambiguous Requests
Keywords: Absent Reference
Desire Reasoning
Language Development
Verbal Negation

The current study explored young children’s ability to use past linguistic information to make pragmatic inferences in a referentially ambiguous situation. Eighty-three 2.5-year-old and 3- year-old children heard a speaker convey her preference for an absent object, using either negative (i.e., “I do not like ducks”) or affirmative (i.e., “I like ducks”) sentences. When two objects become perceptually present (i.e., duck and turtle), the speaker gave an ambiguous request (“Can you give one to me?”). Results showed that three-year-old children were successful in using the speaker’s past affirmative information to reason about which object she desired, however, inferencing abilities were hindered following negative sentences. Two and a half-year-old children did not succeed with neither affirmative nor negative sentences. This work provides important insight into how young children interpret implicit verbal messages to make inferences about another person’s communicative request.
Developing an Intelligent Robot Control Architecture for Autonomous Exploration in Urban Search and Rescue
Keywords: autonomous robot exploration
deep reinforcement learning
partially observable Markov Decision Process
urban search and rescue

The urban search and rescue (USAR) task is a very time sensitive operation which occurs in environments with high uncertainty. The task of a robot in USAR is to explore unknown and cluttered environments and identify any potential victims within the environments. In this thesis, an autonomous controller is presented which utilizes a hierarchical partially observable Markov Decision Process approach to model the environment uncertainty inside a robot’s decision-making scheme. Additionally, an intelligent exploration technique for USAR which utilizes deep reinforcement learning is proposed. The aim of these two techniques is to allow a robot to perform the full USAR task autonomously without the assistance of a human operator and to also follow an efficient exploration strategy which assists in the faster discovery of potential victims. Several experiments were conducted in USAR-like environments to validate the performance and robustness of each technique.
Enzymatic Oxidation for Value-Added Applications of Hemicellulose Streams
Keywords: Biorefinery
Carbohydrate-Active Enzymes
Cross-linker
Hemicellulose
Lignocellulose
Thermoset resin

Hemicellulose is a largely untapped resource generated as a by-product of forestry and agriculture industries amenable to enzymatic activation for value-added applications. Hemicellulose can be modified to prepare dialdehyde polyol cross-linkers as an alternative to toxic petroleum derived chemicals such as glyoxal which is commonly used for polyol film strengthening and hydrogel formation. A chemo-enzymatic pathway was developed to convert galactoglucomannan oligosaccharides into dialdehyde polyol cross-linkers using lactose as a model. Enzymatic oxidation using glucooligosaccharide oxidase introduced a reducing end acid with high conversion in 6.5 hours. Amidation using an ethylendiamine linker achieved a 37% yield of dilactobionamide in 4 hours. This configuration allowed oxidation of terminal galactose units using galactose oxidase yielding nearly complete conversion to a dialdehyde in 6 hours. Initial cross-linking of poly(vinyl alcohol) was attempted in DMSO with some promise. Activation by galactose oxidase also enabled increased reactivity of lactose toward diamines for thermoset resin applications.
Swallowing Misandry: A Survey of the Discursive Strategies of r/TheRedPill on Reddit
Keywords: Anti-Feminism
Geek
Internet
Misogyny
Reddit
Trolling

The Red Pill (r/theredpill) (TRP) subreddit lies at the heart of an interconnected network of misogynistic blogs and websites known as the manosphere. It disseminates radical anti-feminist and discriminatory content across Reddit and the broader internet. Acknowledging the community’s staggering size - with membership that numbers in the hundreds of thousands - this research fills a gap in standalone investigations into the toxic subreddit. Using mixed-methods critical discourse analysis (CDA), qualitative and quantitative research methods identify how misogynistic ideologies are constructed, consumed, and exchanged by RedPills on their virtual platform, Reddit. This study does not seek to define their discursive strategies as uniquely RedPill. Instead, it situates them in the context of a growing community based in gendered rage and the validation of violence. As result, it reveals the complex affordances Reddit provides, to create, engage, and disseminate RedPill discourses online.