Using Semiconductor Nanocrystals to Drive Redox Enzymes with Light

Nanocrystals are an emergent strategy for providing electrons to redox enzymes for catalysis. In this dissertation I present my work on the investigation of how nanocrystals can be used to drive active site chemistry of two different enzymes. In the first project I present for the first time the direct coupling of cadmium sulfide nanorods (CdS NRs) to a CO2 reduction enzyme for the creation of new carbon-carbon bonds using light. Under optimal conditions, the maximum turnover frequency (TOFmax) for CO2&nbsp;reduction is similar to that obtained in the native system where the native electron donor ferredoxin is used; however, high excitation frequencies are needed to reach TOFmax&nbsp;resulting in low quantum yields of 1%. The electron transfer dynamics are investigated as a means to understand this limitation on quantum yield, and we find that the electron transfer rates are dependent on whether the enzyme is bound to reactants. The implications of this new finding are discussed within the context of available crystal structures for the enzyme, and conclusions are drawn about the nature of nanocrystal-protein interactions when the enzymatic catalyst undergoes dynamic conformational changes during light-driven turnover. In the second project I present work performed to promote fast electron transfer in a more well-studied system of CdS NRs and Hydrogenase enzyme (CaI). In this work I substitute an ultrashort, sulfide ligand in place of more conventional 3-mercaptopropionate (MPA) at the interface of the nanocrystal and enzyme to shorten the tunneling barrier to electron transfer. The excited state decay of the CdS-CaI complex is investigated to determine the quantum efficiency of electron transfer (QEET). The QEET is then compared with light-driven H₂ production to understand the overall impact of ultrashort ligands on the photocatalytic activity. This work concludes with a summary of these important findings and a projection for the future implementation of nanocrystals in photochemical schemes where biological enzymes are used as catalysts.</p

Closed Aromatic Tubes-Capsularenes

In this study, we describe a synthetic method for incorporating arenes into closed tubes that we name capsularenes. First, we prepared vase-shaped molecular baskets 4–7. The baskets comprise a benzene base fused to three bicycle[2.2.1]heptane rings that extend into phthalimide (4), naphthalimide (6), and anthraceneimide sides (7), each carrying a dimethoxyethane acetal group. In the presence of catalytic trifluoroacetic acid (TFA), the acetals at top of 4, 6 and 7 change into aliphatic aldehydes followed by their intramolecular cyclization into 1,3,5-trioxane (1H NMR spectroscopy). Such ring closure is nearly a quantitative process that furnishes differently sized capsularenes 1 (0.7×0.9 nm), 8 (0.7×1.1 nm;) and 9 (0.7×1.4 nm;) characterized by X-Ray crystallography, microcrystal electron diffraction, UV/Vis, fluorescence, cyclic voltammetry, and thermogravimetry. With exceptional rigidity, unique topology, great thermal stability, and perhaps tuneable optoelectronic characteristics, capsularenes hold promise for the construction of novel organic electronic devices

Protocol for Pilot Cluster RCT of Project Respect: A school-based intervention to prevent dating and relationship violence and address health inequalities among young people

Background Dating and relationship violence (DRV) – intimate partner violence during adolescence – encompasses physical, sexual and emotional abuse. DRV is associated with a range of adverse health outcomes including injuries, sexually transmitted infections, adolescent pregnancy and mental health issues. Experiencing DRV also predicts both victimisation and perpetration of partner violence in adulthood. Prevention targeting early adolescence is important because this is when dating behaviours begin, behavioural norms become established and DRV starts to manifest. Despite high rates of DRV victimisation in England, from 22-48% among girls and 12-27% among boys ages 14-17 who report intimate relationships, no RCTs of DRV prevention programmes have taken place in the UK. Informed by two school-based interventions that have shown promising results in RCTs in the United States – Safe Dates and Shifting Boundaries – Project Respect aims to optimise and pilot a DRV prevention programme for secondary schools in England. Methods Design: Optimisation and pilot cluster RCT. Trial will include a process evaluation and assess the feasibility of conducting a phase III RCT with embedded economic evaluation. Cognitive interviewing will inform survey development. Participants: Optimisation involves four schools and pilot RCT involves six (four intervention, two control). All are secondary schools in England. Baseline surveys conducted with students in Years 8 and 9 (ages 12-14). Follow-up surveys conducted with the same cohort, 16 months post-baseline. Optimisation sessions to inform intervention and research methods will involve consultations with stakeholders, including young people. Intervention: School staff training, including guidance on reviewing school policies and addressing ‘hotspots’ for DRV and gender-based harassment; information for parents; informing students of a help-seeking app; and a classroom curriculum for students in years 9 and 10, including a student-led campaign. Primary Outcome: The primary outcome of the pilot RCT will be whether progression to a phase III RCT is justified. Testing within the pilot will also determine which of two existing scales is optimal for assessing DRV victimisation and perpetration in a phase III RCT. Discussion This will be the first RCT of an intervention to prevent DRV in the UK. If findings indicate feasibility and acceptability, we will undertake planning for a phase III RCT of effectiveness. Trial registration ISRCTN, ISRCTN 65324176. Registered 8 June 2017, https://doi.org/10.1186/ISRCTN6532417

Utilization of Genomic Tumor Profiling in Pediatric Liquid Tumors: A Clinical Series

Hematologic tumors are mostly treated with chemotherapies that have poor toxicity profiles. While molecular tumor profiling can expand therapeutic options, our understanding of potential targetable drivers comes from studies of adult liquid tumors, which does not necessarily translate to efficacious treatment in pediatric liquid tumors. There is also no consensus on when profiling should be performed and its use in guiding therapies. We describe a single institution’s experience in integrating profiling for liquid tumors. Pediatric patients diagnosed with leukemia or lymphoma and who underwent tumor profiling were retrospectively reviewed. Ten (83.3%) patients had relapsed disease prior to tumor profiling. Eleven (91.7%) patients had targetable alterations identified on profiling, and three (25%) received targeted therapy based on these variants. Of the three patients that received targeted therapy, two (66.7%) were living, and one (33.3%) decreased. For a portion of our relapsing and/or treatment-refractory patients, genetic profiling was feasible and useful in tailoring therapy to obtain stable or remission states. Practitioners may hesitate to deviate from the ‘standard of therapy’, resulting in the underutilization of profiling results. Prospective studies should identify actionable genetic variants found more frequently in pediatric liquid tumors and explore the benefits of proactive tumor profiling prior to the first relapse

Testicular torsion: A retrospective investigation of predictors of surgical outcomes and of remaining controversies.

INTRODUCTION: Testicular torsion (TT), a common surgical emergency worldwide, is typically treated with orchiectomy or orchiopexy. It is widely accepted that the chance of salvaging the testicle declines with time and degree of torsion. The impact of ethnicity on outcome is less well understood, and the association between weather and onset of TT remains a controversy. OBJECTIVES: It is important to know the signs of TT so that appropriate treatment can be given quickly. The purpose of this study was to provide a detailed analysis of registered cases of TT in adolescent patients diagnosed at a single institution to better understand the association between clinical indicators and surgical outcomes and to examine some remaining controversies in the literature on TT. STUDY DESIGN: A retrospective chart review was conducted, using medical records from the present institution. Data were collected for 165 patients who met the following inclusion criteria: 1) adolescent males between 10 and 18 years of age at the time of diagnosis, and 2) TT between January 2001 and June 2013. RESULTS: Of the 165 patients, 38% had orchiectomies. Patients with orchiectomies had longer wait times for surgery (p \u3c 0.0001)-but not greater driving times, driving distances, or degrees of torsion-than those with orchiopexies (Table). Yet, among patients who waited less than the median wait time to surgery (197 min), patients with orchiectomies had greater degrees of torsion than did those with orchiopexies (p = 0.02). Assuming that patients without reference to presence of bell clapper deformity in their medical notes did not have the deformity, those with orchiectomies were less likely to have bell clapper deformity than were those with orchiopexies (p \u3c 0.01). Although mean atmospheric temperature was unassociated with onset of TT and with surgical outcome in general, patients without bell clapper deformity had TT on relatively colder days (p = 0.02). DISCUSSION AND CONCLUSION: Wait time to surgery positively correlates with orchiectomy. Early identification and intervention is vital to testicular salvage. As the degree of torsion increases, the blood supply to the affected testis decreases and the time required to inflict testicular vascular damage decreases. Our results showed the presence of the bell clapper deformity moderated the relationship between temperature and TT: Those without the deformity had torsions on colder days than did those with the deformity. A comprehensive multi-centered study could help draw further conclusions regarding temperature correlation and the bell clapper deformity

sj-docx-1-urj-10.1177_03915603231166722 – Supplemental material for Utility of preoperative urine cultures and cystoscopies before ureteral reimplantation in pediatrics

Supplemental material, sj-docx-1-urj-10.1177_03915603231166722 for Utility of preoperative urine cultures and cystoscopies before ureteral reimplantation in pediatrics by Erin Davis, Dawson Hinkley, Mark E Quiring, Tyler Hamby, Kristy J Reyes and Kirk Pinto in Urologia Journal</p

Addressing Motivations and Barriers to Research Involvement during Medical School among Osteopathic Medical Students in the United States

Involvement in research is regarded as a high-impact educational practice, which, for medical professionals, is associated with sharpened critical thinking and life-long learning skills, greater appreciation for evidence-based medicine, and better clinical competence scores. However, there are limited data regarding the research experience and/or interest among osteopathic medical students in the United States despite a rapidly increasing enrollment and expansion of the number of osteopathic medical schools. Thus, we administered an electronic survey examining prior research experience, interests, and perceptions about research participation during medical school to four successive classes of incoming first-year osteopathic medical students. We also performed focus groups with rising third-year osteopathic medical students around the topic of perceived barriers to and potential enablers of promoting research participation. This yielded a survey addendum where first-year osteopathic medical students provided feedback on the likelihood of specific incentives/enablers to encourage participation in research during medical school. Overall, osteopathic medical students are interested in research, view research experience as valuable, and perceive research experience as beneficial to future career development. Students perceive that the primary barrier to involvement in research is a potential negative impact upon performance in coursework. Feedback on the likelihood of specific enablers/incentives was also garnered. Our findings from a single institution may have important implications in defining the prior experiences and perceptions held by first-year osteopathic medical students. Specifically, our study indicates that research experiences intentionally designed with (1) a strong likelihood of gaining a publication, (2) financial compensation, and (3) the opportunity for short-term involvement, a flexible time commitment, and/or a dedicated time period are most likely to encourage research participation by osteopathic medical students

Addressing Motivations and Barriers to Research Involvement during Medical School among Osteopathic Medical Students in the United States

Involvement in research is regarded as a high-impact educational practice, which, for medical professionals, is associated with sharpened critical thinking and life-long learning skills, greater appreciation for evidence-based medicine, and better clinical competence scores. However, there are limited data regarding the research experience and/or interest among osteopathic medical students in the United States despite a rapidly increasing enrollment and expansion of the number of osteopathic medical schools. Thus, we administered an electronic survey examining prior research experience, interests, and perceptions about research participation during medical school to four successive classes of incoming first-year osteopathic medical students. We also performed focus groups with rising third-year osteopathic medical students around the topic of perceived barriers to and potential enablers of promoting research participation. This yielded a survey addendum where first-year osteopathic medical students provided feedback on the likelihood of specific incentives/enablers to encourage participation in research during medical school. Overall, osteopathic medical students are interested in research, view research experience as valuable, and perceive research experience as beneficial to future career development. Students perceive that the primary barrier to involvement in research is a potential negative impact upon performance in coursework. Feedback on the likelihood of specific enablers/incentives was also garnered. Our findings from a single institution may have important implications in defining the prior experiences and perceptions held by first-year osteopathic medical students. Specifically, our study indicates that research experiences intentionally designed with (1) a strong likelihood of gaining a publication, (2) financial compensation, and (3) the opportunity for short-term involvement, a flexible time commitment, and/or a dedicated time period are most likely to encourage research participation by osteopathic medical students