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Emphysema-associated Autoreactive Antibodies Exacerbate Post-Lung Transplant Ischemia-Reperfusion Injury.
No full textChronic obstructive pulmonary disease-associated chronic inflammation has been shown to lead to an autoimmune phenotype characterized in part by the presence of lung autoreactive antibodies. We hypothesized that ischemia-reperfusion injury (IRI) liberates epitopes that would facilitate preexisting autoantibody binding, thereby exacerbating lung injury after transplant. We induced emphysema in C57BL/6 mice through 6 months of cigarette smoke (CS) exposure. Mice with CS exposure had significantly elevated serum autoantibodies compared with non-smoke-exposed age-matched (NS) mice. To determine the impact of a full preexisting autoantibody repertoire on IRI, we transplanted BALB/c donor lungs into NS or CS recipients and analyzed grafts 48 hours after transplant. CS recipients had significantly increased lung injury and immune cell infiltration after transplant. Immunofluorescence staining revealed increased IgM, IgG, and C3d deposition in CS recipients. To exclude confounding alloreactivity and confirm the role of preexisting autoantibodies in IRI, syngeneic Rag1-/- (recombination-activating protein 1-knockout) transplants were performed in which recipients were reconstituted with pooled serum from CS or NS mice. Serum from CS-exposed mice significantly increased IRI compared with control mice, with trends in antibody and C3d deposition similar to those seen in allografts. These data demonstrate that pretransplant CS exposure is associated with increased IgM/IgG autoantibodies, which, upon transplant, bind to the donor lung, activate complement, and exacerbate post-transplant IRI
"Sexual Hookups via Dating Apps: A Qualitative Study Exploring the Experiences of Black Men Who Have Sex with Men in Florida
No full textChronic infusions of mecamylamine into the medial habenula: Effects on nicotine self-administration in rats.
No full textThe habenula is an epithalamic structure through which descending connections go from the telencephalon to the brainstem, putting it in a key location to provide feedback control over the ascending projections from the brainstem to the telencephalon. The medial habenula has a high concentration of nicotinic receptors. We assessed the role of medial habenular nicotinic receptors for nicotine self-administration (SA) in female young adult Sprague-Dawley rats. The rats had bilateral chronic infusion cannulae placed into the medial habenula nucleus. Each cannula was connected to a slow delivery osmotic minipump to chronically infuse mecamylamine (100 µg/side/day) or vehicle for four consecutive weeks. The rats were tested for nicotine SA for the first two weeks of mecamylamine infusion. Then, they had one week of enforced abstinence, during which they had no access to the nicotine SA. Finally, they had one week of resumed nicotine SA access. There was a significantly differential mecamylamine effects in animals with lower and higher pretreatment baseline nicotine SA. Rats with lower baseline nicotine SA levels showed a nearly significant mecamylamine-induced reduction in SA while those with higher baseline levels of SA showed a significant mecamylamine-induced increase in nicotine SA. This study determined that medial habenular nicotinic receptors are important for nicotine reinforcement. Baseline level of performance makes a crucial difference for the involvement of habenular mechanisms in nicotine reinforcement with nicotinic activation being important for maintaining nicotine self-administration for those with lower levels of baseline self-administration and the opposite effect with subjects with higher levels of baseline self-administration
Dynamic Models of Innovation and Learning
No full textThis dissertation analyzes three dynamic models of innovation. The primary focus of the analysis of each model is to highlight the role of endogenous mechanisms---such as observational learning and product market competition---in determining firms' R&D incentives, the speed of innovation, and the efficiency of equilibrium investment. In Chapter 2 of this dissertation, entitled "Learning and the Timing of New Technology Adoption," I develop a continuous-time model in which two asymmetric firms (incumbent and challenger) decide whether to adopt an innovation of uncertain quality; and if so, when. Early adoption is valuable, as it comes with the possibility of generating a first-mover advantage. However, early adoption comes at the price of greater uncertainty because the innovation’s true quality can be learned only by observing market performance. In particular, firms learn through a process of market experimentation by which the innovation’s true quality is revealed at a rate proportional to first-mover sales. Through this endogenous learning channel, the flow of information becomes inextricably linked to market structure, which I show has significant implications for equilibrium pricing incentives and the dynamics of innovation diffusion. In particular, my results provides an information-theoretic explanation for why established incumbents, despite possessing substantial innovative ability, are disproportionately slow to respond to disruptive innovation—commonly referred to as the Innovator’s Dilemma.In Chapter 3 of this dissertation, entitled "The Role of Market Structure in Competitive Experimentation," analyzes the strategic incentives of firms to trade-off investment into new versus existing technology. Specifically, I develop a continuous-time model in which two firms choose how to allocate a stock of resources toward either R&D (to develop an possible innovation) or current production (to maximize short-term competitiveness). From a technical standpoint, this is the first model of strategic experimentation in which direct payoff externalities arise through endogenous product market interaction. In terms of empirical contribution, my model provides an explanation for (1) the sensitivity of results in empirical work on R&D competition to industry specification and (2) the seemingly paradoxical decisions of historically innovative companies (e.g. Polaroid, RCA, Xerox) to abandon R&D highly-promising new technologies. Finally, the model be used for policy analysis—namely, to evaluate the effect of horizontal mergers on innovation and welfare. Specifically, my results provide a micro-foundation for conceptual arguments made in recent high-profile merger cases (e.g. Dow/DuPont) based on an “innovation theory of harm," by which a statically pro-competitive merger may be viewed as dynamically anti-competitive due to its negative effects on dynamic innovation incentives. In Chapter 4 of this dissertation, entitled ``Leadership and the Value of Persistence,'' which is co-authored with James Anton and Dennis Yao, Co-authored work with James Anton (Duke Fuqua) and Dennis Yao (Harvard Business School) expands the scope of my existing research to include organizational incentives for innovation and the economics of leadership. In a project called ``Leadership and the Value of Persistence,'' we seek to answer the following question: "What is the value of having a persistent leader in an organization?" To make this question precise, we develop and analyze a dynamic model of organizational innovation. In the model, a leader faces a sequence of projects and wants to motivate self-interested managers to work on them so that they can succeed and generate value for the organization. The key strategic tension is that individual managers only internalize the portion of project returns they receive, but the leader internalizes the project’s value to the entire organization. In equilibrium, leaders use persistence (i.e. the refusal to give up on failed projects) for several reasons. First, persistence helps overcome the problem of moral hazard in teams by creating dynamic incentives for self-interested managers to work on projects of low individual value but high organizational value. Second, we show that persistence can be used to credibly communicate private information about high value projects. Intuitively, a leader’s decision to persist after failure provides good news to managers about the project’s value which, in turn, motivates effort. However, persistence can also exacerbate the problem of moral hazard by creating strategic incentives for managers to "experiment with failure" by shirking on current projects in order to learn about the project’s value through the leader’s persistence decision.</p
Characterizing and Influencing Intracellular Transport
No full textFor over 200 years, cell function and behavior has been the subject of significant interest. Although microscopic, mammalian cells are fantastically complicated and need to overcome tremendous environmental inertia to maintain homeostasis, such as facilitating ion gradients and intracellular transport, the movement of cargo through a viscous, crowded cytosol. This latter point is especially important because many diseases, including Alzheimer’s disease, are associated with aberrant transport. Thus, determining how a cell responds to environmental stimuli is critical to building an understanding of fundamental biophysics and working toward future curative measures for transport-related disease.This dissertation begins with a high-level, epidemiological perspective on the co-occurrence of pulmonary diseases in the United States with pneumoconiosis to contextualize microscopic cell responses to damage with macroscopic outcomes. Pneumoconiosis is caused by inhaled dusts and nanomaterials, which can become embedded in and inflame lung tissues. We found that pneumoconiosis is associated with increased rates of chronic obstructive pulmonary disease (COPD), lung cancer, and pneumonia at time of death. When we combined pneumoconiosis diagnoses with the known covariate of smoking history, smokers with pneumoconiosis had the highest rate of COPD in our data, indicating a potential synergistic effect of lung damage.
Interestingly, we found that smoking history and pneumoconiosis were more associated with lung cancer and pneumonia, respectively. Through presented case studies in non-mining/construction occupations, we note that specific pneumoconioses can occur on local scales, demonstrating that even if nanomaterials are too varied to appear in an aggregate population, the risks of increased disease rate as a result of microscopic lung injury are still present. This is essential for future regulation and policy decisions as nanomaterial production continually increases.
To further explore microscopic cell responses to controlled stimuli, we used particle tracking microscopy to follow trafficked organelles and evaluate how the cell uses intracellular transport and reacts to disruptions. The classic approach to analyzing particle tracking data is the mean squared displacement (MSD). Despite its ubiquity, recent work has shown that the MSD is a flawed method because it is unstable with respect to noise, curve fitting choices, and observation window. Here, we present a novel tracking framework that uses a Bayesian changepoint segmentation strategy and then infers population motility from segment velocities. This method avoids the use of MSDs and is efficient and stable in response to trajectories of different quality and length.
We demonstrate this software on tracked lysosomes in epithelial cells. We found that there is a clear difference in the frequency of motion for lysosomes depending on where in the cell they were located, with lysosomes in the perinuclear region moving less often than those in the periphery. This is an extremely important finding because it robustly distinguishes these two regions over thousands of lysosome observations and much of the current particle tracking literature ignores region as a factor, potentially exposing any results to selection bias. Separately, we found that the size of lysosomes, which was controlled with sucrose-induced osmotic swelling, had no effect on transport frequency; however, the speed of large lysosomes was slower than with small lysosomes.
Next, we generalize our tracking system to include all vesicles, rather than only lysosomes. With these conditions, we present an exciting new result: disruption of the endoplasmic reticulum with palmitate, a fatty acid found at elevated levels in patients with diabetes and obesity, significantly decreases vesicle motility. This effect was independent of any reduction in ATP levels or cell viability and appears to be associated with the distortion of the ER we observed under these conditions. This result points to areas of future research in the biophysical complications associated with these diseases and further underscores recent work detailing the extensive interactions between the ER and endocytic vesicles.
Paired with this analysis, we also observed that macromolecular crowding has no effect on directed transport through the reduction of ribosome concentration, indicating that directed intracellular transport is quite efficient despite significant obstacles in the cytosol. Looking further at the cytoskeleton, we show that disruption of actin filaments and microtubules both decrease vesicle motility as expected. However, we found that disruption of intermediate filament organization with withaferin A significantly decreases vesicle motility in a dose-dependent fashion. Unlike microtubules and actin filaments, there are no molecular motors associated with intermediate filaments, so this result may be tied to cytoskeletal interactions and merits further exploration.
In summary, this dissertation details analyses that explore and characterize disruptions to cellular homeostasis. We first provide an updated perspective of dust inhalation diseases in the United States to provide context for cell damage on a macroscopic level and advocate for intentional regulation of nanomaterials as production and exposure risk increase. We also demonstrate an effective Bayesian particle tracking analysis alternative to the mean squared displacement, which overcomes the latter’s limitations. We then use this new tool to learn significant new information about intracellular transport, particularly that there are regional distinctions in vesicle behavior and that ER disruption with palmitate causes a dramatic decrease in transport without affecting viability. Overall, we are most excited for the potential for this analysis to be used across a variety of problems and disciplines and look forward to its implementation.
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A microtiter peg lid with ziggurat geometry for medium-throughput antibiotic testing and in situ imaging of biofilms
No full textCOVID-19 vaccination intention and activation among health care system employees: A mixed methods study.
No full textBackgroundAchieving high COVID-19 vaccination rates among employees is necessary to prevent outbreaks in health care settings. The goal of the study was to produce actionable and timely evidence about factors underlying the intention and decisions to obtain the COVID-19 vaccine by employees.MethodsThe study was conducted from December 2020 - May 2021 with employees from a VA health care system in Southeastern US. The study used a convergent mixed methods design comprising two main activities: a cross-sectional survey conducted prior to COVID-19 vaccine distribution, and semi-structured interviews conducted 4-6 months after vaccine distribution. Data were collected about participant characteristics, vaccination intention prior to distribution, vaccination decision post-distribution, determinants of vaccination intention and decision, activating factors, sources of information and intervention needs. Data from the survey and interviews were analyzed separately and integrated narratively in the discussion.ResultsPrior to vaccine distribution, 77% of employees wanted to be vaccinated. Post vaccine distribution, we identified 5 distinct decision-making groups: 1) vaccine believers who actively sought vaccination and included those sometimes described as "immunization advocates", 2) go along to get along (GATGA) individuals who got vaccinated but did not actively seek it, 3) cautious acceptors who got the COVID-19 vaccine after some delay, 4) fence sitters who remained uncertain about getting vaccinated, and 5) vaccine refusers who actively rejected the COVID-19 vaccine. Participants identifying with Black or multiple races were more likely to express hesitancy in their vaccination intention.ConclusionThe findings of our study highlight distinct decision-making profiles associated with COVID-19 vaccination among employees of a VA health care system, and provide tailored recommendations to reduce vaccine hesitancy in this population
Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents.
No full textCalcineurin is important for fungal virulence and a potential antifungal target, but compounds targeting calcineurin, such as FK506, are immunosuppressive. Here we report the crystal structures of calcineurin catalytic (CnA) and regulatory (CnB) subunits complexed with FK506 and the FK506-binding protein (FKBP12) from human fungal pathogens (Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans and Coccidioides immitis). Fungal calcineurin complexes are similar to the mammalian complex, but comparison of fungal and human FKBP12 (hFKBP12) reveals conformational differences in the 40s and 80s loops. NMR analysis, molecular dynamic simulations, and mutations of the A. fumigatus CnA/CnB-FK506-FKBP12-complex identify a Phe88 residue, not conserved in hFKBP12, as critical for binding and inhibition of fungal calcineurin. These differences enable us to develop a less immunosuppressive FK506 analog, APX879, with an acetohydrazine substitution of the C22-carbonyl of FK506. APX879 exhibits reduced immunosuppressive activity and retains broad-spectrum antifungal activity and efficacy in a murine model of invasive fungal infection
Test-of-Cure After Treatment of Pharyngeal Gonorrhea in Durham, North Carolina, 2021-2022.
No full textBackgroundIn December 2020, the Centers for Disease Control and Prevention updated its treatment guidelines for gonococcal infection and, for the first time, recommended universal test-of-cure for all individuals treated for pharyngeal gonorrhea. After the release of these guidelines, data are lacking on rates of return for the test-of-cure, particularly in populations other than men who have sex with men.MethodsWe analyzed the demographic characteristics, clinical characteristics, rate of return for the recommended test-of-cure, and percent positivity for Neisseria gonorrhoeae on repeat pharyngeal specimens at a local public health department in Durham, NC.ResultsOf 101 individuals treated for pharyngeal gonorrhea between March 2021 and April 2022, 54.5% were men, 71.2% Black or African American, and 58.4% between the ages of 20 and 29 years. Most identified as either women who have sex with men (38.6%), men who have sex with men (24.8%), or men who have sex with women (22.8%). Of these individuals, 41 (40.6%) returned for a test-of-cure, with LGBTQ+ individuals more likely to return than men who have sex with women and women who have sex with men. Of those who returned for the test-of-cure, 4.9% of pharyngeal samples were equivocal and 2.4% positive for N. gonorrhoeae by nucleic acid amplification testing, likely reflecting false-positive tests.ConclusionDespite recommendations to perform a test-of-cure 7 to 14 days after treatment of pharyngeal gonorrhea, rates of return continue to be low. Alternative strategies should be investigated to increase test-of-cure rates
Patient characteristics of smokers undergoing lumbar spine surgery: an analysis from the Quality Outcomes Database.
No full textOBJECTIVE In this analysis the authors compare the characteristics of smokers to nonsmokers using demographic, socioeconomic, and comorbidity variables. They also investigate which of these characteristics are most strongly associated with smoking status. Finally, the authors investigate whether the association between known patient risk factors and disability outcome is differentially modified by patient smoking status for those who have undergone surgery for lumbar degeneration. METHODS A total of 7547 patients undergoing degenerative lumbar surgery were entered into a prospective multicenter registry (Quality Outcomes Database [QOD]). A retrospective analysis of the prospectively collected data was conducted. Patients were dichotomized as smokers (current smokers) and nonsmokers. Multivariable logistic regression analysis fitted for patient smoking status and subsequent measurement of variable importance was performed to identify the strongest patient characteristics associated with smoking status. Multivariable linear regression models fitted for 12-month Oswestry Disability Index (ODI) scores in subsets of smokers and nonsmokers was performed to investigate whether differential effects of risk factors by smoking status might be present. RESULTS In total, 18% (n = 1365) of patients were smokers and 82% (n = 6182) were nonsmokers. In a multivariable logistic regression analysis, the factors significantly associated with patients' smoking status were sex (p < 0.0001), age (p < 0.0001), body mass index (p < 0.0001), educational status (p < 0.0001), insurance status (p < 0.001), and employment/occupation (p = 0.0024). Patients with diabetes had lowers odds of being a smoker (p = 0.0008), while patients with coronary artery disease had greater odds of being a smoker (p = 0.044). Patients' propensity for smoking was also significantly associated with higher American Society of Anesthesiologists (ASA) class (p < 0.0001), anterior-alone surgical approach (p = 0.018), greater number of levels (p = 0.0246), decompression only (p = 0.0001), and higher baseline ODI score (p < 0.0001). In a multivariable proportional odds logistic regression model, the adjusted odds ratio of risk factors and direction of improvement in 12-month ODI scores remained similar between the subsets of smokers and nonsmokers. CONCLUSIONS Using a large, national, multiinstitutional registry, the authors described the profile of patients who undergo lumbar spine surgery and its association with their smoking status. Compared with nonsmokers, smokers were younger, male, nondiabetic, nonobese patients presenting with leg pain more so than back pain, with higher ASA classes, higher disability, less education, more likely to be unemployed, and with Medicaid/uninsured insurance status. Smoking status did not affect the association between these risk factors and 12-month ODI outcome, suggesting that interventions for modifiable risk factors are equally efficacious between smokers and nonsmokers