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Indiana University-Purdue University Indianapolis (IUPUI) / The human genome generates a vast number of functionally and structurally diverse noncoding transcripts, incorporated into complex networks which modulate the activity of classic pathways. Long noncoding RNAs (lncRNA) have been shown to exhibit diverse regulatory roles in various physiological and pathological processes. Hypoxia, a key feature of the tumor microenvironment, triggers adaptive responses in cancer cells that involve hundreds of genes. While the coding component of hypoxia signaling has been extensively studied, much less information is available regarding its noncoding arm. My doctoral work identified and functionally characterized a novel hypoxia-inducible lncRNAs encoded from the miR193b-host gene (MIR193BHG) locus, on chromosome 16. In the pursuit of understanding how MIR193BHG responds to hypoxia, we discovered a more complex transcriptional control of MIR193BHG by hypoxia. Ectopic expression of MIR193BHG in breast cancer cell lines in vitro and in xenografts significantly represses cell invasion, as well as the metastasis to lung and liver. Conversely, inhibition of MIR193BHG promotes cancer cell invasiveness and metastasis. RNAseq followed by pathway analysis revealed that MIR193BHG is a negative modulator of cholesterol biosynthesis pathway. MIR193BHG exerts a highly coordinated effect on the expression of cholesterol biosynthetic genes which leads to a measurable impact on the total cellular cholesterol content. The role of MIR193BHG in cholesterol metabolism also provided a mechanistic explanation for the sex maturation associated SNPs located in vicinity of this gene locus. Our work also provided preliminary insights into the functional mechanism of MIR193BHG by showing that its modulation of genes in cholesterol synthesis is predominantly at transcriptional level. Overall, my dissertation project identified a non-canonical hypoxia-inducible lncRNA, MIR193BHG, which modulates breast cancer invasion and metastasis via finetuning of cholesterol synthesis.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19890号 / 医博第4139号 / 新制||医||1016(附属図書館) / 32967 / 京都大学大学院医学研究科医学専攻 / (主査)教授 川上 浩司, 教授 福原 俊一, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Thesis advisor: Scott D. Slotnick / We are able to consciously remember an incredible amount of information for long periods of time (Brady et al., 2008, 2013). Furthermore, we often think about our memories in terms of how successful we are in retrieving them, such as vividly recalling the smell of your grandmother’s cooking. However, we can also identify the times when we have forgotten information, such as misremembering the name of an acquaintance or misplacing your car keys. Such instances of forgetting have been suggested to be caused by inhibitory processes acting on associated information, such as the inhibitory processing shown in retrieval-induced forgetting where the retrieval of specific items leads to forgetting related information (Anderson et al., 2004; Wimber et al., 2015). Thus, long-term memory is said to rely on both accurately retrieving specific details and inhibiting potentially distracting information. In Chapter 1, I demonstrate that specificity of long-term memory depends on inhibiting related information through a series of behavioral experiments investigating item memory for faces and abstract shapes. In Chapter 2 and Chapter 3, I examine the neural regions associated with long-term memory specificity and inhibitory processing by focusing on the functional roles of the hippocampus and the prefrontal cortex, two key regions associated with long-term memory. In Chapter 2, I provide evidence that the hippocampus is associated with memory specificity by demonstrating that distinct regions of the hippocampus are associated with memory for different visual field locations. Furthermore, I provide evidence that the hippocampus operates in continuous manner during recollection (i.e., conscious retrieval of details). In Chapter 3, I demonstrate that the prefrontal cortex can inhibit both the hippocampus and language processing regions during retrieval of distracting information during episodic and semantic memory, respectively. / Thesis (PhD) — Boston College, 2019. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Psychology.

Background Long QT syndrome (LQTS) is characterized by a prolonged QT interval on the electrocardiogram (ECG), a risk for sudden cardiac death. A simple 'rule of thumb' method states that if a patient's heart rate is between 60-100 bpm, the QT interval should not be more than half the R-R interval. The clinical accuracy of this method has not been tested in the elderly. Objectives To determine if the 'rule of thumb' to calculate QT interval prolongation, is accurate, compared to the corrected QT interval calculated using Bazett's formula. Secondary objectives include the prevalence of long QT and risk factors for QT prolongation. Methods The QT interval was calculated using Bazett's formula, and the 'rule of thumb' method, from ECG's collected from patients over 60 years old, on their first visit to a geriatric clinical service. Only data from patients with heart rates in the range 60-100 were analyzed. Medications and electrolyte levels were recorded. Results A total of 1000 ECGs were collected. 776 ECGs were included in the study. Prevalence of prolonged QT interval was 37.8% using Bazett's formula. Compared to Bazett's formula, the 'rule of thumb' method had a sensitivity of 65.2% and a specificity of 96.9%. ECG computer analysis calculated QTc was available for 42.5% of the cases and had a sensitivity of 58.1% and specificity of 95.3% compared to Bazett's formula. Of the 23.3% of patients taking medications known to prolong the QT interval only 38.6% had a prolonged QT interval. There was a significant association between QT interval prolongation and hypokalaemia. Conclusion The 'rule of thumb' method to determine QT interval prolongation, has high specificity but low sensitivity. This bedside measure is similar in accuracy to QT determination using an ECG computer analysis calculation in this population of older persons. / MT 2019

This dissertation offers a revisionist account of American regionalist fiction. In particular, it contests prevailing diagnoses of the genre as bourgeois nostalgia by locating within its content and form a radical utopian impulse. By drawing out their engagement with socialist, feminist, anti-racist, and environmental protection movements, this project shows how regionalist texts perform both the utopian work of envisioning progressive futures and the necessarily regionalist work of orienting and charting a path toward those futures on a localized scale. Although our historical understanding of social movements during the Long Gilded Age is largely framed in the Nationalist and (proto-)Progressive politics of much overtly utopian fiction, comparative readings of William Dean Howells, Sarah Orne Jewett, Charlotte Perkins Gilman, Charles W. Chesnutt, Sutton E. Griggs, W. E. B. Du Bois, and Kate Chopin reveal within regionalist fiction a more radically democratic model for social change. This suggests, in part, that regionalist writers of the 1870s through the 1910s imagined the local rather than the national as the scale on which social change could and should be carried out.

The Palliative and Therapeutic Harmonization (PATH) program was designed to help frail older adults and their family members prepare for and make medical decisions, in the context of frailty and dementia. This sandwich thesis includes three manuscripts that present the findings from a mixed methods study exploring the implementation and outcomes of the PATH program, in three long-term care (LTC) home settings. The purpose of the first sub study was to describe both the perceived need for the PATH program, and initial reactions following its training and implementation. Quantitative surveys and qualitative interviews with bereaved family members showed that prior to implementation, they were mostly satisfied with their relatives’ end-of-life care. Through qualitative interviews, clinical leaders shared a positive impression of the training and PATH principles. They also explained how the PATH program could help them improve palliative and end-of-life care planning and communication with residents and families. In the second sub study, qualitative interviews were conducted with family members to learn about their experiences with and perceived outcomes from the PATH program. All family members had a positive experience. They shared perceived outcomes such as, opportunities to share and learn about their relative’s health status and trajectory, creating a mutual understanding of directions for care, and receiving support and reassurance for health care decision making. Finally, the purpose of the third sub study was to describe both the perceived outcomes of the staff who implemented the PATH program, and differences in documenting residents’ advance care plans and discussions. Staff described both personal and practice related outcomes. In addition, documentation around advance care planning changed with the program’s implementation. Overall, the PATH program offered frail older adults, their family members and their professional caregivers an opportunity to communicate about and prepare to make decisions for palliative and end-of-life care. / Dissertation / Doctor of Philosophy (PhD)

An electrochemical detection method based on long range surface plasmon waveguides is proposed and demonstrated in this integrated article thesis. This dissertation uses CYTOP gold (Au) waveguides supporting long range surface plasmon polaritons (LRSPPs) in conjunction with grating couplers as well as Au waveguides embedded on a one-dimensional photonic crystal (1DPC) supporting Bloch LRSPPs integrated grating couplers. Grating couplers for Au stripe waveguides embedded in Cytop are demonstrated and analyzed. Grating couplers are used in a broadside coupling scheme where a laser beam incident on a stripe of Au on Cytop. The use of gratings for excitation of LRSPPs simplifies optical alignment and does not require high-quality input and output edge facets. Over a broad operating wavelength range, optical experiments are performed to demonstrate coupling loss and determine the efficiency of grating coupling using both a cleaved bow-tie PM fiber and a lensed PM fiber. The coupling loss and grating coupling efficiency of both types of fibers are also calculated numerically. Fluoropolymers with refractive indices close to water, such as CYTOP, are widely used to make waveguide biosensors today. Due to its low glass transition temperature, CYTOP presents limitations to fabrication processes. A truncated 1D photonic crystal may replace a low-index polymer cladding such as CYTOP to support Bloch LRSPPs within the bandgap of the 1DPC over limited wavenumbers and wavelength range. As a result of the high sensitivity of Au stripe Bloch LRSPP waveguide biosensors and their compatibility with high levels of integration, microelectrode systems that can be integrated with such optical biosensors are examined. A chip bearing a Au LRSPP waveguide that can also function as a working electrode (WE), a Pt counter electrode (CE), and Pt/Cu electrical contact pads, is used to demonstrate the electrochemical performance of LRSPPs waveguides. The cyclic voltammetry measurements were performed at different scan rates and concentrations of potassium ferricyanide as the redox species on Au LRSPPs waveguides. By fitting our experimental data to the Randles-Sevcik equation, we find the diffusion coefficient of potassium ferricyanide. The results from CV measurements obtained from chips are compared with commercial macroscopic electrodes. The CV measurements are also compared with theoretical results computed using the Butler-Volmer equation to determine the rate constant of the redox species at zero potential. A waveguide containing a stripe of Au that propagates infrared surface plasmon polaritons (SPPs), acting simultaneously as an electrode in a three-electrode electrochemical cell is also examined. Under SPP excitation, cyclic voltammetry was measured as a function of incident optical power and wavelength (1350 nm). In oxidation and reduction reactions, energetic electrons are separated from energetic holes. Under SPP excitation, redox current densities increase by 10×. With the SPP power, the oxidation, reduction, and equilibrium potentials drop by as much as 2× and separate in correlation with the photon energy. According to electrochemical impedance spectroscopy, charge transfer resistance dropped by almost 2× under SPP excitation. During SPP excitation, the temperature of the working electrode is monitored in situ and independent control experiments are performed to isolate thermal effects. Measurements of chronoamperometry with SPPs modulated at 600 Hz yield a rapid current response modulated at the same frequency, ruling out thermally enhanced mass transport. The observation is attributed to the opening of optically controlled non-equilibrium redox channels associated with the energetic carrier transfer to the redox species. During CV and chronoamperometry measurements, convolutional voltammetry is performed by monitoring the SPP output power versus the applied voltage. Using both experimental and theoretical methods, we demonstrate that the SPP output power is proportional to the electrochemical current convolution. A SPP voltammogram confirms that signal changes are mainly caused by differences in refractive index between reduced and oxidized forms of redox species. In addition, we demonstrate that energetic carriers resulted from SPP absorption significantly improved electrochemical sensitivity. As a complementary electrochemical technique, convolutional voltammetry is useful since the signal is related directly to the concentration of electroactive species on the working electrode (WE) and independent of the scan rate. As a probe of electrochemistry taking place in waveguides, surface plasmon polaritons (SPPs) propagating along one are sensitive. In such a waveguide, the optical output power is proportional to the time convolution of the electrochemical current density, eliminating the need to calculate the latter a posteriori via numerical integration. It is demonstrated that a waveguide WE provide an optical response that can be experimentally validated by chronoamperometry and cyclic voltammetry measurements under SPP excitation for a few potassium ferricyanide (redox species) concentrations in potassium nitrate (electrolyte) and various scan rates. Cyclic voltammetry measurements taken under increasing SPP power produce a regime where SPPs no longer act solely as the probe, but also act as a pump, producing energetic electrons and holes via their absorption in the WE. The energetic carriers enhance (10×) redox current densities as well as the convolution signal measured directly as the optical output power over time.

The long-term care (LTC) sector in Canada has experienced high numbers of COVID-19 deaths. However, there is a paucity of data on the impact of COVID-19 in LTC by different socio- demographic variables and in LTC homes within different regions. Additionally, the question remains as to how exactly and by how much the pandemic has impacted mortality in LTC in comparison to previous years’ mortality. Ranges for expected mortality by sex, province, and age, for the 2020-21 fiscal year were determined by creating forecasts and confidence intervals based on mortality trends in the preceding four fiscal years. These ranges were then compared to the actual mortality data in 2020-21. Comparisons between expected ranges and actual data were also conducted for the number of active residents, admissions, and discharges in LTC by sex, province, and age. Further, mortality ratios were created and studied by sex, province, age, and health region/authority/local health integration network. Overall, the number of deaths in LTC in Canada increased beyond the expected ranges in quarter one and three of 2020-21, and the patterns in death ratios were similar. Increases were exceptional in comparison to the peaks in deaths in previous years for specific variables, but not all variables. Most commonly, the number of active residents and admissions decreased in 2020-21 and the number of discharges from LTC did not change in quarter one and three and decreased in quarter two and four. However, importantly, these trends also varied across variables. This was the first study to comprehensively examine mortality due to COVID-19 in LTC overall, and by multiple socio- demographic variables while elucidating the complexity in the study of mortality in LTC. Further research is required to concretely understand mortality in LTC by different variables and regions. / Thesis / Master of Arts (MA) / This study examined mortality due to COVID-19 from April 2020 to March 2021 in Canadian long-term care (LTC) homes by sex, age, province, and health region. Ranges of predicted values for mortality were created from mortality data from previous years and then compared with actual mortality. The number of active residents, admissions, and discharges were also examined by sex, age, and province to factor for changes in the population at risk. Overall, mortality increased in some quarters (April-June 2020 and October-December 2020) but was not always exceptional, as similar mortality rates had been observed in the four years prior to the pandemic. Also, the increase in mortality was seen mostly among younger residents (65 to 85); mortality remaining stable for the 85+. Further research is still required to better understand mortality in LTC by regional characteristics.

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