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Antiviral response drives epithelial metabolic reprogramming to promote secondary bacterial infection
No full textIncreasing evidence shows that viral infections predispose the host to the acquisition of acute or chronic bacterial infections. Viral-bacterial co-infections are often linked to more severe outcomes, leading to prolonged stays in intensive care units and more severe clinical symptoms (1,2). These viral-bacterial co-infections happen at multiple host sites, including the airways (3–19). Unfortunately, the research focused on elucidating the mechanisms that lead viral infection in the airway epithelium to increase the susceptibility to developing secondary bacterial infection is scarce. Several lines of evidence support a role of the antiviral response in increasing the likelihood of secondary bacterial infections (20–23). Previous work in our laboratory has shown that the antiviral response triggered during the infection by respiratory syncytial virus (RSV) predisposes to the development of Pseudomonas aeruginosa chronic infection, specifically in the chronic respiratory disease model Cystic Fibrosis (CF) (22).
Here we will show our new findings on how the antiviral response driven by IFN signaling induces the expression of Interferon-Stimulated Genes (ISGs), a wide array of genes that are meant to inhibit viral infection and are involved in a wide range of cellular processes, including metabolism. We used a lentivirus-based ISG screen to identify ISGs that promote chronic P. aeruginosa infection in an in vitro model of CF bronchial epithelial cells. This ISG screen led us to the identification of 5 hit ISGs, and we further dissected the mechanism by which the hit hexokinase 2 (HK2), stimulates P. aeruginosa biofilm formation. HK2 encodes the first rate-limiting enzyme in glycolysis associated with an extension of glycolysis, known as aerobic glycolysis or Warburg effect (WE), which funnels glucose toward the synthesis of L-lactate. We observed that the increase of L-lactate and its apical secretion enhanced P. aeruginosa biofilm growth. These results suggest that the antiviral interferon response drives reprogramming of the host which supports secondary bacterial infections.
Understanding how viral infections predispose to secondary bacterial infections opens new avenues for treatments based on the host, being a priority in the context of chronic bacterial infections affecting people with chronic lung diseases, for which the efficacy of current treatments is limited
Essays on Environmental, Urban, and Transportation Economics
No full textOn-road transportation is one of the most important sources of urban greenhouse gas emissions and local pollution. This dissertation consists of three essays that explore the efficiency and distributional effects of policies in alleviating emissions from the urban transportation sector. I examine three policies in each chapter: electric vehicles (EVs), reformulated gasoline, and public transportation.
Chapter 1 studies the distribution of environmental benefits from EV across space. I develop a structural model of the U.S. auto market and use data from California to study household decisions on EV adoption across multiple vehicles and trip-specific vehicle selection. Combining the model-predicted probability of EV driving with simulated optimal travel routes, I construct a measure of the cumulative EV mileage at a highly granular geographic level. I show that higher-income communities receive more benefits; however, this disparity is less pronounced than EV adoption. I compare the EV purchasing subsidies with charging station investments and find that investment in charging infrastructures generates more environmental benefits and delivers a more equitable distribution.
Chapter 2 investigates the impact of gasoline content regulation on consumer demand in China. The empirical design takes advantage of the unique market structure and policy-induced changes in gasoline formulation. Using detailed gas station-level data, I find that consumers respond positively to standard upgrades and substitute higher-emission gasoline for lower-emission ones. I present evidence to suggest that the effects are driven by the preference for the higher environmental value of the new gasoline and discuss the policy implications.
Chapter 3 compares the impacts of expanding the subway network with revising subway prices in the context of Beijing, China. I find that both subway expansion and the fare change significantly impact gasoline consumption in the short run. However, the effect of subway expansion is larger and more durable. A cost-benefit calculation shows that expanding the subway reduces driving more cost-effectively than fare changes
Metal-Mediated Propargylic C–H Functionalization of Alkynes
No full textHerein is described the invention and development of several novel strategies for the transformation of simple alkynes into useful products via metal-mediated propargylic C–H functionalization. First a brief introduction into π-acid catalysis is presented in the context of allylic and propargylic functionalization, including the Wang group’s use and development of a substituted cyclopentadienyliron dicarbonyl species as a catalyst for propargylic hydroxyalkylation. Next is described the behavior of various organoiron intermediates from this system, and their use in other related organic transformations. Most notably among these are various cycloaddition processes for the production of densely substituted organoiron dihydropyrrolonyl- and dihyropyranyl- species that could be further transformed into organic products using divergent demetallation strategies. Next, ongoing efforts to leverage the stoichiometric intermediates for propargylic oxidation are presented in the context of reaction development. Finally, our initial discoveries with a related iridium-catalyzed system for propargylic C–H stannylation and germanylation are presented
Design Study Evaluating Impact of Gap Loss on Inductors with Nanocrystalline Cores
No full textAs decarbonization efforts continue and electric vehicle (EV) technology matures, en-
gineers are challenged with developing compact and efficient power electronics. Magnetic
components, including inductors, are critical to the operation of power conversion systems.
To increase power density and efficiency, it is ideal to 1) reduce the size of magnetic com-
ponents, as they are often the largest contributors to the system’s physical footprint, and 2)
minimize component power losses. A common inductor design technique is placing an air gap
in the core, allowing designers to tune the inductance and allow higher levels of magnetic field
without saturation. The inclusion of gaps can increase the total magnetic core loss beyond
those predicted by common models such as the Steinmetz equation, creating the need for
accurate gap loss models. In this study, finite-element simulation and physical experiments
are used to validate assumptions about the sources of gap loss and its dependence on gap
length. A sample nanocrystalline inductor is tested over a range of gap lengths under fixed
operating conditions, with core losses measured and compared to a selected gap loss model.
The model was then integrated into a multi-objective optimization framework to study the
fitness of nanocrystalline cores against ferrite cores at different switching frequencies. This
work finds that gap losses can increase the total loss of nanocrystalline inductors by up to
an order of magnitude as frequency increases, implying that consideration of gap losses is
vital to selecting the appropriate core material for design applications
Tumor-Targeting Nanoparticles for Improved Cancer Therapy
No full textIn the past decade, advancements in nanotechnology and our growing understanding of cancer biology and nano-bio interactions have led to the development of various nanoparticles (NPs). However, the targeting efficiency of existing NPs is still too limited to be translated into clinic. Developing new tumor targeting NPs and unveiling the targeting mechanism emerges as an ideal strategy to overcome the limitations in the current paradigm of tumor-targeted delivery and improve the therapeutic effect of anticancer agents.
An ultra-small NP was first developed based on 5-azacytidine (AZA)-conjugated polymer (PAZA) for the co-delivery of AZA and BMN673. AZA conjugation significantly reduced the nanoparticle size to 12 nm, allowing efficient tumor targeting through more effective enhanced permeation and retention (EPR) effect and penetration via the in-situ formation of fibronectin-enriched protein corona in the blood, which mediated transcytosis through ITGA5 receptor on tumor cells. An RNAseq-guided mechanistic study demonstrated that PAZA carrier reduced the DNA repair induced by BMN673, sensitizing HR-proficient non-small cell lung cancer (NSCLC) to BMN673. Furthermore, BMN/PAZA enhanced both innate and adaptive antitumor immune response, which was more effective at a lower dosage.
Despite the improved tumor targeting with the ultra-small PAZA NPs, it is still somewhat subjected to the limitation of EPR effect. To target tumors through a mechanism independent of the EPR effect, we developed a biodegradable nanocarrier coated with chondroitin sulfate (PCL-CP). PCL-CP NPs were highly effective in tumor targeting and penetration through both EPR and CD44-mediated transcytosis in tumor endothelial cells and tumor cells, resulting in superior efficiency in active tumor targeting and tumor penetration. More importantly, we discovered a novel pharmacological target, iRhom1, and elucidated its role in chemo-immuno-resistance. However, there are no small molecule drugs available for inhibiting iRhom1. Better synergy could be achieved by combining chemotherapy drugs with gene therapeutics for "undruggable" targets. PCL-CP was further modified to be effective in co-delivering iRhom1 pre-siRNA (pre-siiRhom) and chemotherapeutic drugs. Co-delivery of pre-siiRhom1 and a chemotherapy agent (DOX or CPT-SAHA) led to significantly enhanced antitumor efficacy and activated tumor immune microenvironment in multiple cancer models
Brain Mechanisms of Attention and Motor Deficits after Stroke
No full textAccomplishing most goals in daily life requires cooperation and coordination of the spatial attention networks to identify appropriate targets in the environment, and the motor network to plan and execute an action to the target. Strokes can disrupt these systems, as common deficits include spatial neglect and hemiparesis. Current stroke therapies leave many patients with lasting disabilities, and they are limited by our understanding of how these brain networks are affected by lesions and how they relate to subsequent impairments. This information may help us shape future rehabilitation strategies that target individual-specific deficits. In this thesis, we investigate the effects of stroke on spatial attention and motor planning
and employ novel technologies and techniques to examine these systems. In the first study, we investigate the changes in neural activation leading to spatial neglect in stroke patients. We built an objective measure of neglect using a combined augmented reality electroencephalography
(AR-EEG) system. This portable, adaptable device records neural correlates of a visual target detection task through EEG. In stroke patients with neglect, we found lateralized brain activation patterns spanning the frontal-parietal electrodes in response to contralesional targets,
particularly in alpha and beta frequency bands. We can also
detect neglect in individual patients with high accuracy using just their task-related EEGs. We find that asymmetric activation of the attention networks correlates with diminished spatial attention abilities. In the second study, we investigate the changes in non-primary motor area connectivity leading to component deficits of movement in subcortical stroke patients. We designed a planar reaching task in a robotic exoskeleton where transcranial
magnetic stimulation (TMS) was delivered to frontal and parietal locations during movement planning. Healthy controls’ kinematics were consistently perturbed by suprathreshold stimulation over the contralateral dorsal premotor cortex. By contrast, nearly every stroke patient
had a unique response to different stimulation parameters, revealing that even small subcortical strokes can elicit large-scale functional circuit-level changes between these preparatory areas and motor cortex, creating vastly different behavioral outcomes. Together, these studies provide insight into the variable mechanistic effects of stroke on brain activation and connectivity and are the first step to personalizing rehabilitation therapies
Design and evaluation of a dietary management system.
No full textObjective: Hypertension, a prevalent global health challenge, often suffers from inadequate dietary management among patients. Current dietary management apps still have a lot of room for improvement when providing service to hypertension patients. This study proposes developing and evaluating a novel mobile phone-based diet management system specifically designed for hypertensive patients. This system aims to improve the pertinence for hypertensive users and improve app usability through Enhanced UI/UX, voice-based and image-based input modalities.
Methods: This research used a within-subjects study design and fly-on-the-wall observation to obtain user feedback on image-based and voice-based input.
Conclusion: The experimental results are consistent with the previous hypothesis that voice-based input and image-based input can improve app usability to some extent. However, the UI design of the app still needs some optimization in order for the user to use the app correctly without additional guidance
Validation and Translation of a Novel Wheelchair Rolling Resistance Test Method
No full textManual wheelchairs are an essential device for many people to actively participate in daily life, but the high prevalence of upper limb (UL) pain and injury that increases with time directly affects quality of life for many manual wheelchair users. Clinical practice guidelines recommend minimizing frequency and force of UL repetitive task such as wheelchair propulsion. The force required for propulsion is primarily due to rolling resistance (RR), the energy loss from the contact of wheels with the surface, which can be quantified through testing.
Current RR test methods are primarily system level tests, which combine the effect of multiple factors (weight, weight distribution, rear wheels and casters, camber, toe angle) and do not provide the actionable data needed to advise how to lower RR for a specific manual wheelchair user. The need for a component-level RR test was identified by a previous research team, and this team developed drum-based RR test equipment to measure individual rear wheel and caster RR in a highly repeatable manner, and with precise measurement of RR forces that could be helpful to guide clinical decisions. The next steps towards realizing the benefits of this test and the goals of this dissertation were to validate that the test predicts RR compared to accepted system-level test methods, and to use the data to support the goals of stakeholders such as users, providers, manufacturers and researchers in reducing RR.
To validate that component-level test results provide necessary precision and accuracy compared with gold-standard test methods, validation studies were completed comparing drum RR with treadmill drag tests, and over-ground and treadmill SmartWheel RR on multiple surfaces (Chapters 2 & 3). To demonstrate the value of the component-level RR measurements, several studies were carried out. Component-level RR testing was used in collaborative wheelchair research to evaluate caster RR after two years of simulated use (Chapter 4) and this project is a first step towards translating component-level RR testing into research practice.
To support clinical provision, an online clinical decision support system named RightWheel was developed through a user-centered iterative design process (Chapter 5). A pilot launch study engaged clinicians to use RightWheel, provide feedback and assess usability/perceived usefulness, and confirmed the value of component-level RR with researchers and manufacturers (Chapter 6). Our team believes that validating the RR test method and translating it into use by clinicians, researchers and manufacturers can improve wheelchair product selection, provision, product development and standards
Single-molecule studies of thymine DNA glycosylase interacting with DNA
No full textBase excision repair (BER) is suggested to be the main pathway involved in oxidative DNA demethylation. One such oxidized moiety, 5-formylctyosine (5fC), is recognized and removed by thymine DNA glycosylase (TDG) to generate an abasic site, an intermediate in active demethylation. TDG binds avidly to abasic sites and is product inhibited. Using single molecule fluorescence experiments, we saw TDG slide on unmodified DNA and have specific, stationary binding to 5fC with lifetimes of 7.5 and 72.9 seconds, respectively. Mean squared displacement analysis and a two color TDG experiment indicate that TDG utilizes hopping and sliding in search of a modified base. The catalytically crippled variants, N140A and R275A/L, have a reduced binding lifetime compared to wild type and mean squared displacement (MSD) analysis indicates that R275L/A moves on the DNA with a faster diffusivity. These results indicate that mutating R275, but not N140, interferes with damage recognition by TDG. On DNA containing an undamaged nucleosome, TDG either bypassed, collided by could not bypass or colocalized with the nucleosome after contact. However, truncating the TDG N-terminus significantly reduced the number of interactions with the nucleosome. Additionally, biochemical studies showed that UV-DDB, UV-damaged DNA binding protein the first responder in nucleotide excision repair (NER), can stimulate the turnover of TDG 14-fold as well as displace TDG from an abasic site. Single molecule experiments revealed that TDG and DDB2 colocalize at 5fC. Our findings give insight into how TDG searches for its lesions in long stretches of undamaged DNA and chromatin and indicate that UV-DDB is able to stimulate TDG by facilitated dissociation
Supporting Data for: Segregative Phase Separation of Strong Polyelectrolyte Complexes at High Salt and High Polymer Concentrations
No full textThis dataset contains photographs, thermogravimetric analysis (TGA) profiles, Fourier transform infrared (FTIR) spectra, and nuclear magnetic resonance (NMR) spectra of samples of poly(styrene sulfonate), poly(diallyldimethylammonium), potassium bromide, and water reported in the authors' manuscript "Segregative Phase Separation of Strong Polyelectrolyte Complexes at High Salt and High Polymer Concentrations.