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Synthesis of Covalent Nitro Inhibitors of Mycobacterium Tuberculosis Isocitrate Lyase
No full textM.S.Tuberculosis (TB), ranked among the top ten causes of death worldwide, is still one of the major global health issues. Mycobacterium tuberculosis (Mtb) is the pathogen that causes TB, and humans are the only known reservoir for this disease. Persistent Mtb depends on the glyoxylate shunt, consisting of isocitrate lyase (ICL) and malate synthase, which bypasses two steps of decarboxylation that are otherwise operative in the tricarboxylic acid cycle. Since the glyoxylate shunt is essential for Mtb's survival and adaptation, ICL is an attractive drug target. Covalent inhibitors often demonstrate favorable pharmacokinetic performances, long-lasting active states, and avoidance of drug resistance. 3-Nitropropionate (3-NP) was recently shown to covalent modify Cys191 of Mtb ICL to form a stable thiohydroximate adduct. Unfortunately, the poor selectivity of 3-NP renders it unsuitable for drug development. The current work aims to design a covalent inhibitor that operates through a mechanism similar to 3-NP but with much higher selectivity for ICL. We have proposed that this can be achieved by attachment of 3-NP to a hydroxamic acid moiety, which is expected to anchor the inhibitor to the active-site Mg2+ ion, allowing the nitro group to react with the neighboring Cys191 residue. It is proposed that the hydroxamic acid group could direct the inhibitor more selectively into the target's active site due to tighter binding. Additionally, hydroxamic acids benefit from being less-acidic isosteres of the carboxylic group of the natural substrate, which may aid in penetration of the Mtb cell wall. Two isocitrate analogues containing nitro and hydroxamic acid groups have been designed as potential covalent inhibitors of ICL: 3-(N-hydroxyacetamido)-3-nitropropanoic acid (1) and 4-(hydroxyamino)-3-nitro-4-oxobutanoic acid (2). The difference between these inhibitors is the orientation of hydroxamic acid next to the 3-NP moiety. It is expected that the α-proton next to the two electron-withdrawing groups in 2 would be greatly acidified, and as a result, this inhibitor may more readily exist as the desired nitronate in solution and therefore display greater potency. In this thesis, I designed and attempted multiple synthetic plans to 1 and a synthetic plan that only took four steps to yield 2. Although the hydroxamic acid featuring an internal N–OH as in 1 proved to be too difficult to achieve, the scaffold with a terminal N–OH as in 2 holds promise as an ICL inhibitor with a mode of action similar to 3-NP. The innovative structural combination of nitro group and hydroxamic acid may lead to new classes of covalent inhibitors against ICL.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Cardiovascular Responses to Sugar- and Artificially-Sweetened Beverages During Mechano- and Metabo-Receptor Stimulation
No full textM.S.Objective: Test the hypotheses that consumption of a sugar-sweetened beverage (SSB) would exacerbate cardiovascular responses and attenuate cerebrovascular responses during mechano- and metabo-receptor stimulation compared to an artificially-sweetened beverage (ASB) or water (H2O) ingestion. Methods: Fourteen healthy adults (Age: 24±3 years, 5 females) consumed 500 mL of H2O or SSB (Soda, Mountain Dew®) or ASB (Diet Soda, Mountain Dew®) in a randomized, double-blind study design in a moderate thermal environment (24.5±1.1℃, 21.8±6.0% relative humidity). 20 min after consuming the assigned beverage, subjects completed a 10-min baseline (BL) followed by a 2-min handgrip exercise (HG) at 30% of maximal voluntary contraction and 2 min of post exercise muscle ischemia (PEMI) followed by a 5-min recovery. Heart rate (HR), blood pressure (BP), middle cerebral artery blood velocity (MCAv) and partial pressure of end tidal carbon dioxide (PETCO2) were recorded continuously. Stroke volume (SV) was estimated using Modelflow. Cardiac output (Q) was calculated as HR × SV. Total peripheral resistance (TPR) was calculated as mean BP/Q, and cerebrovascular conductance index (CVCi) was calculated as MCAv/mean BP. Data were analyzed as a change from BL (Δ) to every 30 s of HG and PEMI. Data are reported as Δ M ± SD. Results: At BL, systolic BP was higher in ASB compared to H2O. Diastolic BP and mean BP were higher in ASB compared to SSB and H2O. There were no beverage × time interaction effects or beverage main effects for the changes in all variables during HG and PEMI. There were time main effects for the changes in all the cardiovascular variables during HG and PEMI. A delayed increase in BP was seen following SSB and ASB during HG, and not during PEMI compared to H2O. The increase in MCAv was lower in SSB and ASB during HG and PEMI compared to H2O. Conclusion: Acute ASB consumption induced higher resting BP compared to SSB and H2O intake. However, the cardiovascular responses to mechano- and metabo-receptor stimulation in healthy young adults were not influenced by SSB or ASB consumption in a moderate thermal condition. SSB and ASB consumption induced a lower MCAv during mechano- and metabo-receptor stimulation compared to H2O intake.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Dendritic Fibrous Nano Silica Based Metal Catalysts in Dry Reforming of Methane
No full textM.S.Dry reforming of methane is an endothermic catalytic process that reacts two greenhouse gases, methane and carbon dioxide, to produce syngas (H2 and CO), which can further be used for various energy applications or chemical synthesis. Dendritic fibrous nano silica (DFNS) is a new category of silica with enhanced surface area, controllable pore volume and size, improved accessibility to internal pores and improved structural stability at temperatures up to 800 °C. Here, we first synthesized dendritic silica using an oil in water micro emulsion technique. Synthesis parameters were varied to tune the size and morphology of these structures. DFNS nanopowders with high surface areas (~800 m2/g) were then decorated with nickel (Ni) and other promoter metals including Mg, Ce, and Zr using wet impregnation. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) were used to visualize the metal particle decoration of the silica support. The catalytic activity and stability of the prepared catalysts were then tested and compared. Addition of promoter metals enhanced the conversion of methane and carbon dioxide. The best catalyst was then chosen for a stability test and further characterized after 12 hours of use.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Delirium Risk and Healthcare Utilization Among Homebound Veterans
No full textUB SON, DNP Research ProjectBackground and significance: Delirium is a serious clinical syndrome encountered in geriatric
patients, which leads to higher costs, increased healthcare utilization and mortality. Evaluating
older adults for delirium risk factors, screening, early diagnosis and prevention strategies can
help maintain health.
Purpose and objectives: The Buffalo NY Veterans Administration Home Based Primary Care
(HBPC) team is positioned to work toward minimizing patient delirium risk and improving
outcomes, however the team does not currently screen for delirium risk. The purpose of this
project was to develop a tool to evaluate for delirium risk in the HBPC population and to validate
the tool via a prospective chart review of healthcare use.
Theoretical framework: Neuman’s Systems Model guided this study.
Methods and design: A comprehensive literature review established evidence-based delirium
risk factors and guided tool development. Chart review established delirium risk followed by a
prospective chart review to evaluate healthcare utilization.
Results: Average delirium risk score, based on scale of 0-10 was 6.98, SD 1.51, range 3-10,
suggesting high delirium risk in the sample (n=66). 36.4% of the sample developed delirium
during the chart review period.
Conclusion: HBPC has a high-risk population for delirium development. The sample is
significantly skewed; tool validation though healthcare utilization was unsuccessful.
Future recommendations: HBPC would be better suited to focus efforts on delirium screening
and risk mitigation. Use of the delirium risk assessment tool in traditional primary care may be
helpful in both evaluate delirium risk and evaluating tool validity via healthcare utilization
Impact of An Educational In-Service on Multimodal Postoperative Nausea and Vomiting (PONV) Prophylaxis and Treatment Protocol for Adult Gynecological Surgical Patients
No full textUB SON, DNP Research ProjectPostoperative nausea and vomiting (PONV) is a common and distressing complication for adult gynecological surgery patients undergoing general anesthesia. Research findings support that anesthesia care providers using multimodal PONV prophylaxis and treatment protocols among high-risk, gynecological surgery patients incur a lower incidence of PONV and reduced length of stay in the post-anesthesia care unit (PACU). The purpose of this Doctor of Nursing Practice (DNP) project was to determine the impact of an educational in-service provided to anesthesia providers at a local community hospital in Western New York on use of a multimodal PONV prophylaxis and treatment protocol to decrease incidence of PONV and length of stay in the PACU for adult gynecological surgery patients receiving general anesthesia. Specific aims for this project were to decrease incidence of PONV and decrease PACU length of stay for adult gynecological surgery patients receiving general anesthesia. Pre-intervention, a retrospective chart review monitoring anesthesia provider incidence of PONV and PACU length of stay was performed and a Likert-style scale survey was administered to determine perceived anesthesia provider barriers to a multimodal PONV prophylaxis and treatment protocol. Following the in-service, a second chart review was performed to evaluate the impact of the in-service. Data analysis included independent paired t-tests and Chi-Square correlation tests to determine relationships among variables measured for the chart reviews and descriptive statistics for survey data. Although project findings were not statistically significant, findings provided insight for PONV evidence-based practice guidelines to be brought to the forefront for future research
Development of an Online Preceptor Workshop for the DNP Nurse Anesthesia Program Recruitment and Retention
No full textUB SON, DNP Research ProjectThe purpose of this Doctor of Nursing Practice (DNP) project was to develop an evidence-based
online preceptor workshop for Certified Registered Nurse Anesthetist (CRNA) clinical preceptors
to improve their communication skills, teaching strategies, and clinical education consistency
with Student Registered Nurse Anesthetists (SRNAs). Knowles Theory of Adult Learning served
as the theoretical framework. A webpage was created through web press to host the online
workshop. A 20-item pre-educational survey, a 20-item post-educational survey, and a 24-item
one-month follow up survey were developed and distributed through SurveyMonkey. A Likert
scale was used to measure preceptor responses. A RM-ANOVA was used to measure the means
for each item. A total of 37 CRNAs participated in the pre-workshop survey, 28 CRNAs
completed the workshop and post-workshop survey, and 20 CRNAs completed the one-month
follow up survey. Significant results were noted for the question “please rate your comfort level
with conflict management and resolution with SRNAs.” Mauchly’s test of sphericity assumption
was x2 (2)= (2.594), p=.273. Test within subjects showed [F (1,16) = 6.054, p = 0.026].
Statistically significant results were also noted for the question “I feel I Provide a formal
debriefing of SRNAs performance at the end of every clinical day.” Paired T-test showed
significant results from pre-workshop (M=1.70, SD=1.08) and post-workshop survey reflections
(M=1.15, SD=0.67) conditions t(19) =2.24, p=0.37. The educational intervention showed a
positive impact on clinical preceptor’s communication skills and clinical education consistency.
Future research should include a needs assessment survey focusing on perceived CRNA preceptor
education needs
Patient No-Show Reasons and Strategies for Reducing Patient No-Shows as Perceived by Providers and Staff Working in an Urban Primary Care Clinic in New York City
No full textUB SON, DNP Research ProjectPatient no-shows present major obstacles to the delivery of safe, effective, and quality health
care. The purpose of this qualitative descriptive study was to gain better insight and
understanding regarding reasons for patient no-shows and strategies for reducing patient noshows
as perceived by primary care providers and staff working in an urban primary care clinic
located in New York City (NYC). Kotter’s (2014) Leading Change Model guided this Doctor of
Nursing Practice (DNP) project. Findings resulting from a review health related literature on
patient no-shows guided the development of one semi-structured interview questionnaire for
providers and one semi-structured interview questionnaire for staff. After receiving University at
Buffalo, Institutional Review Board (IRB) approval, two providers and 12 staff members
working at the clinic were voluntarily recruited for study participation. Individual semistructured
interviews were conducted in a private lounge located in the clinic. Interviews were
audiotaped, transcribed verbatim, and then read and reread to ensure transcription accuracy.
Braun and Clarke’s (2006) thematic analysis method was utilized to analyze data. The following
six key themes were identified: Affecting Providers, Affecting Staff, Affecting Patients,
Financial Burdening, Patient Reasoning, and Preventing no-shows. Project findings were
presented and discussed during an interactive educational in-service at the clinic and were
utilized by the providers and staff working together during the in-service to update the clinic’s
current patient no-show policy and procedures
Multi-Scale Deep Learning for Small Object Detection in Whole Slide H&E Stained Images: Tumor Bud Detection in Colorectal Cancer
No full textM.S.The full text PDF of this thesis is embargoed at author's request until 2021-02-19.Whole slide images of hematoxylin and eosin (H&E) stained tissues are widely used in clinical diagnoses as they are inexpensive and easier to obtain. Pathologists diagnosing Colorectal Cancer (CRC) use them to diagnose tumor progression by looking for tumor buds, which are a small group of tumor cells no more than five that exist in the invasive tumor front. Since such small objects cannot be spot at low magnification scale, the pathologists look for the invasive tumor fronts which are considered the ‘hotspots’, then further examine the regions at high magnification scale to manually count the tumor buds. This is a laborious process and is subject to the experience level of the observer. We aim to build a deep convolutional neural network (CNN) system that automates this process to provide more efficient and consistent detection results. The multi-tiered classifier is inspired by the workflow of pathologists that takes steps to target different biological characteristics at different magnification scale. This work is applicable to general small object detection in whole slide histological images, such as mitosis detection in breast cancer tissue or tumor satellite detection in oral cavity cancer.**To request an accessible version of the file(s) associated with this item, contact [email protected]. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.*
Sex Hormone Regulation of Immune Responses: The Impact of Androgen Receptor in Myeloid Cell Function
No full textPh.D.The full text PDF of this dissertation is embargoed at author's request until 2021-02-19.The immune system is a complex system that combines cellular and soluble mediators that recognize numerous microorganisms and destroys pathogens. Although the immune system has evolved to defend the organism against invading pathogens, immune cells are also implicated and deregulated in various disease states. It is increasingly recognized that men and women display differences in disease susceptibility, prevalence and pathogenesis. These include sex disparity in cancer, autoimmunity, allergy and infectious diseases. While the etiology of these diseases differs significantly, their pathogenesis is tightly linked to the immune system. In general, women show enhanced, while men display weaker immune responses. Testosterone has generally been associated with an immunosuppressive effect, while estrogen enhances immune responses. Sex differences in immune responses and disease susceptibility highlight the importance of studying how immune function is regulated by sex hormone signaling, to ultimately understand and treat disease. Here we demonstrate for the first time that androgen receptor (AR) antagonism, a commonly used treatment for prostate cancer, induces functional and metabolic changes in myeloid cells associated with increased immunosuppression and tumor progression (Chapter 2). We further show that sex hormone modulation, such as reducing the ratio of estradiol to testosterone signaling, impairs clearance of urinary tract infection in female mice (Chapter 3). Moreover, we identify that AR is required for monocytic differentiation in the bone marrow (Chapter 4). Finally, we demonstrate that myeloid AR expression impacts T cell development in the thymus (Chapter 5). Our studies add to the growing evidence that sex hormones impact immunity, and that sex hormone manipulations affect the course of diseases