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Objectives: Systemic antibiotics are generally recognized as providing a beneficial impact in treatment of both aggressive and chronic periodontitis. Since strains of periodontal pathogens among periodontitis patients may vary in their antibiotic drug resistance, the American Academy of Periodontology recommends antimicrobial susceptibility testing of suspected periodontal pathogens prior to administration of systemic periodontal antibiotic therapy, to reduce the risk of a treatment failure due to pathogen antibiotic resistance. E-test and MIC Test Strip assays are two in vitro antimicrobial susceptibility testing systems employing plastic- and paper-based, respectively, carriers loaded with predefined antibiotic gradients covering 15 two-fold dilutions. To date, no performance evaluations have been carried out comparing the Etest and MIC Test Strip assays in their ability to assess the in vitro antimicrobial susceptibility of periodontal bacterial pathogens. As a result, the purpose of this study was to compare the in vitro performance of E-test and MIC Test Strip assays in assessing minimal inhibitory concentration (MIC) values of four antibiotics frequently utilized in systemic periodontal antibiotic therapy against 11 fresh clinical subgingival isolates of the putative periodontal pathogen, Prevotella intermedia/ nigrescens, and to compare the distribution of P. intermedia/ nigrescens strains identified with interpretative criteria as "susceptible" and "resistant" to each of the four antibiotics using MIC values determined by the two antimicrobial susceptibility testing methods. Methods: Standardized cell suspensions, equivalent to a 2.0 McFarland turbidity standard, were prepared with 11 fresh clinical isolates of P. intermedia/nigrescens, each recovered from the subgingival microbiota of United States chronic periodontitis subjects, and plated onto to the surfaces of culture plates containing enriched Brucella blood agar. After drying, pairs of antibiotic-impregnated, quantitative, gradient diffusion strips from two manufacturers (E-test, bioMérieux, Durham, NC, USA, and MIC Test Strip, Liofilchem s.r.l., Roseto degli Abruzzi, Italy) for amoxicillin, clindamycin, metronidazole, and doxycycline were each placed apart from each other onto the inoculated enriched Brucella blood agar surfaces, so that an antibiotic test strip from each manufacturer was employed per plate against each P. intermedia/ nigrescens clinical isolate for antibiotic susceptibility testing. After 48-72 hours anaerobic jar incubation, individual MIC values for each antibiotic test strip against P. intermedia/nigrescens were read in μg/ml at the point where the edge of the bacterial inhibition ellipse intersected with the antibiotic test strip. MIC50, MIC90, and MIC range were calculated and compared for each of the test antibiotics, with essential agreement (EA) values determined per test antibiotic for the level of outcome agreement between two antimicrobial susceptibility testing methods. In addition, the identification of antibiotic "susceptible" and "resistant" strains among the P. intermedia/nigrescens clinical isolates was determined for each test antibiotic using MIC interpretative criteria from the MIC interpretative standards developed by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for gram-negative anaerobic bacteria for amoxicillin, clindamycin, and metronidazole findings, and from the French Society of Microbiology breakpoint values for anaerobic disk diffusion testing for doxycycline data. Results: For amoxicillin, higher MIC50 and MIC90 values against the P. intermedia/ nigrescens strains were found with the MIC Test Strip assay than with E-test strips, resulting in a relatively low EA value of 45.5% between the two susceptibility testing methods. A higher percentage of amoxicillin "resistant" P. intermedia/nigrescens strains (72.7%) were identified by MIC Test Strips as compared to E-test strips (54.5%), although both methods found the same proportion of amoxicillin "susceptible" strains (27.3%). For clindamycin, both susceptibility testing methods provided identical MIC values (EA value = 100%), and exactly the same distributions of "susceptible" and "resistant" strains of P. intermedia/nigrescens. For metronidazole, only very poor agreement (EA value = 9.1%) was found between the two susceptibility testing methods, with MIC Test Strips exhibiting markedly higher MIC50 and MIC90 values against P. intermedia/nigrescens as compared to E-test strips. However, the distribution of "susceptible" and "resistant" P. intermedia/ nigrescens were identical between the two susceptibility testing methods. For doxycycline, relatively good agreement (EA value = 72.7%) was found in MIC concentrations between the two susceptibility testing methods, although generally lower MIC values were associated with MIC Test Strips. In addition, identical distributions of "susceptible" and "resistant" P. intermedia/nigrescens were provided by both susceptibility testing methods. Conclusions: Relative to MIC values measured against periodontal strains of P. intermedia/nigrescens, MIC Test Strips gave higher MIC values with amoxicillin and metronidazole, equal MIC values with clindamycin, and lower MIC values with doxycycline, as compared to MIC values measured with the E-test assay. Relative to the identification of antibiotic "susceptible" periodontal P. intermedia/ nigrescens strains, both susceptibility testing methods provided identical findings, suggesting that both methods appear to be interchangeable for clinical decision making in regard to identification of antibiotic-sensitive strains of periodontal P. intermedia/nigrescens. However, for epidemiologic surveillance of drug susceptibility trends, where exact MIC values are important to track over time, the relatively higher proportion of non-exact MIC differences between the two susceptibility testing methods argues against using them interchangeably. Instead, one or the other method should be used consistently for such studies. Further comparative studies of the E-test and MIC Test Strip assays are indicated using other periodontopathic bacterial species besides P. intermedia/ nigrescens, and to assess the reproducibility of MIC values provided by both in vitro susceptibility testing methods over time. / Oral Biology

<p> The carotid body (CB) is the main peripheral chemoreceptor organ that maintains homeostatic control of the O2, CO2, glucose and pH levels in the blood. It is innervated by nerve fibers from the carotid sinus nerve (CSN) that consists of sensory afferents from the petrosal ganglion (PG) and "inhibitory" efferents from the glossopharyngeal nerve (GPN). The efferent innervation forms an elaborate network that is immuno-positive for neuronal nitric oxide synthase (nNOS), and is thought to inhibit the CB via release of nitric oxide (NO). The purpose of this study is to further understand the underlying mechanisms of this inhibition. Since the CB possesses various neurotransmitters, including the excitatory neurotransmitter, acetylcholine (ACh), I tested the hypothesis that the CB drives its own modulation during chemoexcitation by secreting ACh, which would directly act on receptors located on the GPN neurons (GPNs) and lead to nNOS activation via calcium entry and the subsequent release of NO. To address this, molecular and calcium imaging techniques were used to demonstrate the specific types of nicotinic ACh receptors (nAChRs) expressed in GPN neurons. It was shown that GPN neurons expressed the mRNA for ten subunits: α2-α9, excluding α8 and β2-β4 and they responded to ACh and nicotine, a nAChR agonist, in a dose-dependent manner via an increase in intracellular calcium. The EC50 for ACh and nicotine were ~ 9.9 and 20.5 μM respectively. The nicotine-induced calcium transients were inhibited by mecamylamine, a nAChR competitive antagonist, with an IC50 of ~ 1.2 μM. Studies using subunit-specific antagonists, dihydro-β-erythroidine (specific for α4β2 and α3β4 in particular dose ranges) and methyllycaconitine (MLA) and α-bungarotoxin (BTX; both specific for α7) revealed that the major functional nAChR expressed in GPNs were the α4β2 and α3β4 nAChRs. The results of this study show that GPN neurons respond to ACh stimulation with an increase in intracellular calcium and thus raise the possibility that ACh secreted after stimulation/activation of receptors on the CB may contribute to the synthesis of NO and negative feedback inhibition of CB function via stimulation of GPN efferent nerve fibers.</p> / Thesis / Master of Science (MSc)

Background: Individuals with binge eating disorder (BED) experience a loss of control (i.e., poor inhibitory control) during binge eating, where stress is a common antecedent for binge episodes. However, few studies examine acute stress in BED and, to date, psychosocial stress relationships with inhibitory control are unexamined. Purpose: The current study investigated acute psychosocial stress effects on inhibitory control in BED. Additionally, inhibitory control relationships with BED treatment outcome were explored. Methods: Thirty-three individuals with BED were randomized to a stress (n = 17) or no stress condition (n = 16). All completed self-report measures including the Profile of Mood States and the Binge Urge Scale. Following the stressor, individuals completed the Stop-Signal Task (SST), a well-validated measure of inhibitory control. Relationships between post-stress anxiety with inhibitory control and eating pathology were explored. Furthermore, treatment outcome relationships with levels of inhibitory control, and negative urgency (an impulsive personality trait) were explored. Results: In the stress condition, individuals reported increased state anxiety immediately following stress, but experienced a decrease back to baseline levels of anxiety by the end of the SST. Stress resulted in impaired inhibitory control performance on the SST. Binge urges increased across both conditions over time. Measures of inhibitory control and negative urgency did not relate to treatment outcome. Conclusion: This study is novel in directly examining psychosocial stress effects on inhibitory control, which has not been studied in BED. These results show subjective stress effects in BED are short-lived; however, behaviourally, stress has a lingering effect on inhibitory control. Increasing binge urges across the experimental session in the no stress condition suggests a role for generalized anxiety on this impulse. These findings have clinical implications for binge urges as a therapeutic target, and for informing individuals with BED about the implications of stress on their binge eating. / Thesis / Master of Science (MSc)

Background: Lower inhibitory control has been shown to associate with greater risk for obesity in adolescence. On average, females have moderately higher rates of behavioral inhibitory control than males. These difference in inhibitory control across sex may influence overeating and development of obesity. This study examined whether sleep duration and sleep quality are associated with food-related inhibitory control and whether this association is moderated by biological sex. Methods: A total of 59 emerging adults ages 18 to 25 (37 males, 22 females) who had a BMI within the overweight or obese categories (BMI ≥25) completed self-report measures of eating and sleep behavior. Participants completed a Go/NoGo behavioral task to evaluate their inhibitory control when presented with images of high- and low-calorie foods. Results: In general, our hypotheses regarding sex differences were not supported by this study. We did not find a significant association between sleep duration and food-related inhibitory control, nor did we find a significant association between sleep quality and inhibitory control. We did find that poorer sleep quality was associated with greater loss of control eating (p = 0.001). Conclusion: Our findings suggest that sleep quality has notable impacts on food-related inhibitory control. The findings from our study could be utilized in future research towards understanding the complex relationship between sleep duration and quality, inhibitory control, and eating behaviors.

Fearful temperament represents one of the robust predictors of the development of child and adolescent anxiety. Not all children with fearful temperament unvaryingly develop anxiety, however. Diverse processes resulting from the interplay among attention, cognitive control, and motivational system drive the trajectories toward more adaptive or maladaptive directions. In this study, I examined various factors that underlie the association between fearful temperament at age 9 and adolescent anxiety symptoms including attention biases, different components of effortful control, and frontal EEG asymmetry. 78 children participated in this study. Results indicate that fearful temperament at age 9 significantly predicted adolescent anxiety symptoms. This association, however, was moderated by children's effortful control and frontal EEG asymmetry at age 9. Specifically, fear at 9 years predicted adolescent anxiety only when children had low attentional control, low inhibitory control, low activation control, and exhibited greater right activation from baseline to task. The associations between AB and fearful temperament as well as anxiety were not significant. The association between fear at 9 years and sustained AB during adolescence, however, was moderated by children's attentional control, inhibitory control, and frontal EEG asymmetry at age 9. Specifically, fear predicted attention biases away from threat when children had high attentional control, high inhibitory control, and showed greater left activation. The findings will be discussed in terms of the roles of attention biases in the development of anxiety and how different components of effortful control and frontal EEG asymmetry contribute to the resilience process. / Doctor of Philosophy / Anxiety disorders represent one of the most commonly occurring mental health problems in childhood and adolescence. Children who tend to show wariness and distress to negative stimuli are more likely to have anxiety. Not all children with fearful temperament develop anxiety, however. Certain individual characteristics can protect fearful children from having anxiety symptoms. In this study, I examined the roles of attentional biases toward threat (AB), different components of self-regulation (EC), and the asymmetrical frontal brain activation (FA) in changing the relation between fearful temperament and anxiety. 78 children participated in this study. Results indicated that adolescents were at higher risk for anxiety if they showed high fearful temperament at age 9. However, the risk could be attenuated if children were better able to control their attention and behaviors, and exhibited greater left activation from resting to a mildly stressful situation at age 9. In addition, fearful children were better able to direct attention away from threat during adolescence if they were better able to control their attention and behaviors, and exhibited greater left activation from resting to a mildly stressful situation at age 9. The findings provide suggestions for early identification and intervention of children who are more vulnerable to anxiety during adolescence.

Shyness is highly related to internalizing problems. However, not all shy children develop serious internalizing problems (IP). The aim of the current study was to identify the endogenous factors that might contribute to the resilience process from a self-regulation perspective. Participants included 73 children (33 boys; 40girls) who visited the lab at 6 and 9 years of age. Shyness, attentional control (AC), inhibitory control (IC), frontal electroencephalogram (EEG) asymmetry were measured at both 6 and 9 years using age appropriate questionnaires and tasks. Results indicated that age 6 shyness did not directly predict age 9 IP; instead it indirectly predicted IP through age 9 shyness. Neither AC, IC, frontal EEG asymmetry, nor the stability of frontal EEG asymmetry moderated the association between age 6 shyness and age 9 IP. However, there was a positive concurrent association between shyness and IP at 9 years. In addition, AC and IC moderated the shyness-IP association at age 9. Shyness was significantly associated with IP only when children had low AC or IC, but not when children had high AC or IC. / Master of Science / Shyness is highly related to internalizing problems. However, not all shy children develop serious internalizing problems (IP). The aim of the current study was to identify the within-individual factors that might protect children away from having IP from a self-regulation perspective. Participants included 73 children (33 boys; 40girls) who visited the lab at 6 and 9 years of age. Shyness, attentional control (AC), inhibitory control (IC), frontal electroencephalogram (EEG) asymmetry were measured at both 6 and 9 years using age appropriate questionnaires and tasks. Results indicated that children who are shy at 6 years old may not have IP at 9 years old. Instead children who are shy at 6 years old tend to be shy at 9 years old. And those who are shy at 9 years old are more likely to have IP at the same period of time. Neither AC, IC, frontal EEG asymmetry, nor the stability of frontal EEG asymmetry affect the direction or degree of the association between age 6 shyness and age 9 IP. In addition, AC and IC affect the concurrent shyness-IP association at age 9. Shyness was significantly associated with IP only when children had low AC or IC, but not when children had high AC or IC.

As virtual experiences are rapidly substituting a significant proportion of in-person interactions during the COVID pandemic, it is critical to monitor the effect of screen exposure time on developing children’s behavior and nervous system. Screen use boosts information accessibility and, therefore, may delay the development of the inhibitory control networks in children, who are vulnerable to immediate reward-orientated tendencies and not yet capable of controlling their impulsivity. Therefore, it was hypothesized that as children become more exposed to screens, the development of the inhibitory control network would be delayed and their reward sensitivity will be augmented. Using the ABCD Study Data Repository, 8,334 children’s behavioral and neural data (aged 9-11) were included. Robust mediation analysis and correlation analysis were used to investigate how Screen Time interacts with children’s reward-orientated tendency (e.g. Behavioral approach system, BAS) and the brain's inhibitory network. Intrinsic Frontoparietal Network-Striatum (FPN-Striatum) connectivity strength was used as neural indices of the inhibitory control quality in children. Results showed that Screen Time significantly mediated the relationship between BAS and both waves of the intrinsic inhibitory process. A higher BAS was linked to a longer Screen Time and weaker inhibitory network connectivity. This complete/full mediation model indicates that Screen Time negatively influenced the strength of FPN-Striatum connectivity. In conclusion, the study revealed specific behavioral and neural correlates of screen exposure using a large database, and suggested that increasing screen exposure time may impair the inhibitory capability and increase impulsivity in children. / M.S. / The current study explored the effect of daily screen exposure in pre-adolescent children to provide an important springboard for future work in protecting developing children against the negative impacts of screen use, which has increased significantly during the COVID-19 pandemic. Over 8,000 children’s data from the Adolescent Brain Cognitive Development (ABCD) project was included and found that an increased daily screen exposure time is linked to an inefficient inhibitory control system in the brain. As children’s inhibitory control systems are still developing, this negative effect further hinder the maturation of inhibitory-control systems two years later. Given that the virtual movement is irreversible, the results provide scientific evidence that a balance between screen time and non-screen activities is required for developing children.

Yes / Multidrug resistance (MDR) limits the beneficial outcomes of conventional breast cancer chemotherapy. Ras-related nuclear protein (Ran-GTP) plays a key role in these resistance mechanisms, assisting cancer cells to repair damage to DNA. Herein, we investigate the co-delivery of Ran-RCC1 inhibitory peptide (RAN-IP) and doxorubicin (DOX) to breast cancer cells using liposomal nanocarriers. A liposomal delivery system, co-encapsulating DOX, and RAN-IP, was prepared using a thin-film rehydration technique. Dual-loaded liposomes were optimized by systematic modification of formulation variables. Real-Time-Polymerase Chain Reaction was used to determine Ran-GTP mRNA expression. In vitro cell lines were used to evaluate the effect of loaded liposomes on the viability of breast and lung cancer cell lines. In vivo testing was performed on a murine Solid Ehrlich Carcinoma model. RAN-IP reversed the Ran-expression-mediated MDR by inhibiting the Ran DNA damage repair function. Co-administration of RAN-IP enhanced sensitivity of DOX in breast cancer cell lines. Finally, liposome-mediated co-delivery with RAN-IP improved the anti-tumor effect of DOX in tumor-bearing mice when compared to single therapy. This study is the first to show the simultaneous delivery of RAN-IP and DOX using liposomes can be synergistic with DOX and lead to tumor regression in vitro and in vivo.