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DISTINCT TUMOR INFILTRATING TREG LINEAGES A ASSOCIATE WITH RESPONSE TO ANTI-PD1 (NIVOLUMAB) CHECKPOINT BLOCKADE IN NSCLC and IDENTIFYING CD4+ T CELL IMMUNITY ASSOCIATED WITH SARS-COV-2 INFECTION AND VACCINATION THROUGHOUT THE COVID-19 GLOBAL PANDEMIC
Get PDFImmune-checkpoint blocade (ICB) can induce durable clinical responses in a subset of patients, especially those with highly mutated tumors such as lung cancer. Nevertheless, most patients do not respond to ICB. Regulatory T cells (Tregs) may play a role in this lack of response by suppressing tumor-reactive cytotoxic T cells, however the specific mechanisms that lead to this suppression remain elusive. We aim to understand the functional programming and suppressive nature of Tregs in the tumor microenvironment (TME) to define targetable molecules for future biomarker-driven therapeutics. We performed single cell TCRseq/RNAseq on Tregs isolated from resected lung tumor, distal normal lung, and peripheral blood from 15 patients treated with neoadjuvant nivolumab (anti-PD1) and 10 untreated non-small cell lung cancer (NSCLC) patients. We analyzed 71,251 CD4+ FoxP3+ Tregs and performed refined clustering to define distinct Treg subsets. We identified 7 distinct Treg clusters with two of these Treg subsets diverging towards either an activated state, expressing members of the tumor necrosis factor receptor (TNFR) superfamily OX40, 41BB, GITR, or a resting state. We show that responding tumors have a significantly decreased activated Treg score than both non-responding tumors and untreated tumors. These activated Tregs are highly suppressive and may be secondarily influenced by effective ICB therapy through TNFR ligand-receptor interactions with other immune subsets. We also describe Treg tumor antigen-specificity as a driver of high suppressive capacity and aim to define suppression mechanisms unique to tumor antigen-specific TCRs. Together, this study provides an in-depth look at Treg-derived suppressive mechanisms that govern their function in the TME of anti-PD-1-treated vs. untreated tumors. This approach will identify specific targetable biomarkers which could be used to improve ICB response while mitigating off-target immune adverse events by specifically inhibiting a small subset of Tregs without disturbing systemic immune homeostasis
New perspective on the role of complex spikes
Get PDFOur movement requires continual adaptation throughout our lives. The cerebellum is thought to be the site of this adaptation. One of the major inputs to this structure is climbing fiber that induces complex spike (CS) in the Purkinje cells (P-cells). The complex spike is traditionally considered to be the error or teaching signal, which drives synaptic plasticity in the cerebellum and, in turn, drives the gross adaptation that we observe in our lives. In this dissertation, we studied the complex spike to see beyond its traditional role as the error signal.
In Chapter 2, we look at the role of CS as the perturbation signal to the movement. We found that the suppression of simple spikes (SS) in a P-cell by the occurrence of CS alters the saccade trajectory by pulling the eyes toward the preferential direction of the CS encoding of that cell. From this result, we hypothesized on the role of CS as the stochastic perturbation signal, which allows the system to sample the broader space of movement and to possibly lead to an optimal adaptation.
In Chapter 3, we show that there are two groups of the P-cells that receive different information from their olivary input: one group receives the sensory information, and the other group receives the movement information of the intended movement. We saw these two groups also have different modulation of SS, leading us to hypothesize the role of CS as the maintainer of the SS, which reflects the adaptation that a cell has learned.
In Chapter 4, we present the new software that runs the eye behavior task and undergirds the whole system of behavior-electrophysiology. Overall system layout and internal architecture of the software are discussed, in addition to the advantages it has over the previous system
PASS_E2E_TEST_SUBMISSION_JOURNAL:Fri May 31 2024 00:16:17 GMT+0000 (Coordinated Universal Time)
No full textAMATEUR SCIENCE: COMMUNITIES AND CONNECTIONS IN THE EVERYDAY LIFE
Get PDFThe following is an exploration of various scientific and personal topics, mainly focused upon niche communities and amateur science. These stories tend to go overlooked and underappreciated, and my goal as a writer is to introduce them to a wider audience. This collection includes topics such as Bigfoot enthusiasts, the tool-assisted speedrun community, and the science behind pole dancing. I also consider my connection to these communities and hobbies, and how my personal experiences may influence my views
Maladaptive Repair in Acute Kidney Injury
No full textAcute kidney injury (AKI) affects approximately 15-20% hospitalized individuals (1). In critically ill patients, the development and progression of AKI is associated with 40-60% mortality (1). In addition, survivors of AKI have a fourfold higher risk of developing chronic kidney disease (CKD) and end stage kidney disease (ESKD) (2). Evidence from preclinical studies of AKI suggests that maladaptive repair of injured renal tubular cells may lead to persistent inflammation and fibrosis, thus mediating the progression of AKI and the AKI-to-CKD transition (3, 4). Currently, this maladaptive repair can only be captured by investigating the kidney tissue. Therefore, it is challenging to characterize the prevalence of maladaptive repair and determine its prognostic values in large cohorts of patients with AKI. This knowledge gap has further hampered therapeutic development in this area.
The goal of these studies is to determine the etiological relationship between maladaptive kidney repair and complications after AKI. First, by simultaneous interrogating the kidney tissue transcriptome and plasma proteome in individuals with AKI, we identified novel plasma biomarkers of renal tubule maladaptive repair that are associated with progression of AKI after cardiac surgery. Second, we demonstrated that the increase in established biomarkers of kidney injury and inflammation over time is associated with kidney maladaptive repair after AKI and may prognosticate the AKI-to-CKD transition. These biomarkers may help establish the etiological association between maladaptive kidney repair and complications after AKI. In addition, they may serve as pharmacodynamic endpoint in facilitating drug development in this area.
To further elucidate the role of inflammation in maladaptive repair, we investigated kidney graft outcomes in recipients from deceased donors receiving dialysis for severe AKI. These deceased donors had a high prevalence of kidney maladaptive repair, leading to severe AKI requiring dialysis. In addition, their kidney transplant recipients uniformly received aggressive immunosuppression after transplantation, allowing us to observe kidney outcomes when inflammation is greatly attenuated. We found that these kidney recipients do not have higher risk of long-term graft loss. This suggests inflammation may be an important mediator of long-term adverse kidney outcomes after maladaptive repair, and may be a therapeutic target for drugs preventing long-term outcomes after AKI
NAVIGATING THE PATH TO GLOBAL CLIMATE ACTION: INSIGHTS ON STAKEHOLDER PERSPECTIVES AND POLICY IMPERATIVES RELATED TO THE EUROPEAN UNION’S CARBON BORDER ADJUSTMENT MECHANISM
Get PDFThe European Union implemented the Carbon Border Adjustment Mechanism (CBAM) in 2023, marking the first implementation of a previously theoretical border carbon adjustment. Due to the implications on global climate policy and decarbonization efforts, understanding the impacts of CBAM on various stakeholders is necessary to ensure its effectiveness and global acceptance. This research examines the perspectives of stakeholders on CBAM through interviews with policy experts and industry operators and analysis of public comments. These methods reveal that trade economics (carbon leakage, trade impacts, competition) are top concerns across stakeholders. These stakeholders also emphasize the importance of effective system functioning. Issues such as robust measurement, reporting, and verification standards and streamlined reporting processes are crucial. Companies emerged as key stakeholders whose position can influence the success of a policy. Therefore, it is necessary to take into account their concerns, namely, rising costs and maintaining market access. The findings of this research highlight the need for a formal process for managing and monitoring these concerns. The findings also suggest that as border carbon adjustments become more widespread, mechanisms should be included to allow for policy revision and adjustment. This flexibility can allow for a policy to be refined based on insights gained from both its own failures and successes and to increase interoperability with emerging global policies
ACTIGRAPHIC ASSESSMENT OF SLEEP AND CIRCADIAN REST/ACTIVITY RHYTHMS IN PERSONS WITH ALZHEIMER'S DISEASE AND THEIR CAREGIVERS
No full textObjective
To evaluate and describe the differences and changes in sleep and nonparametric circadian parameters in persons with memory impairment and their care partners (memory care dyads) participating in the CAPABLE-Family program.
Methods
A systematic review and meta-analysis were performed to assess the existing literature related to sleep parameter differences between persons with memory impairment and their care partners. To further understand differences in sleep and circadian parameters in the memory care dyad, as well as whether members of the dyad experienced differential benefit from the intervention, participants were recruited from CAPABLE-Family, a randomized, waitlist-controlled pilot trial aiming to improve physical function in persons with coexisting functional disability and memory impairment. Persons with memory impairment and their care partners wore an actigraph for one week pre- and post-intervention. We compared descriptive statistics and examined differences between members of the dyad at pre- and post-intervention. Additionally, we estimated 3-level linear mixed effects models (MLE) for four sleep outcomes: Total sleep time, sleep efficiency, wake after sleep onset, and sleep onset latency; and three circadian outcomes: Interdaily stability (IS), intradaily variability (IV), and relative amplitude (RA).
Results
The systematic review and meta-analysis showed persons with memory impairment had longer total sleep time but poorer sleep efficiency than their care partners. Thirty-four and 20 participants completed pre- and post-intervention actigraphy, respectively. Persons with memory impairment had longer total sleep time than their care partners, however there were no significant differences in sleep efficiency, wake after sleep onset, or sleep onset latency. Persons with memory impairment had more stable rhythms (higher IS) than care partners at baseline. Post intervention, care partner rest/activity rhythms became more stable aligning more closely with the persons with memory impairment. Persons with memory impairment had greater fragmentation (higher IV) than their care partners. Post-intervention, marginal differences were detected showing a positive benefit in care partners (lower IV). Care dyads had equivalent values of RA at baseline with care partners showing a slight increase in RA following the intervention.
Conclusion
Targeting functional ability in persons with memory impairment, as is done in CAPABLE-Family, may have beneficial effects on care partner circadian rest/activity rhythms. Sleep parameters appeared to be less affected by the CAPABLE-Family intervention, with persons with memory impairment sleeping longer than their care partners. Future controlled research and a larger sample size are warranted
ADVANCES IN MEASUREMENT TECHNIQUES AND MICROMECHANICAL MODELING FOR GRANULAR MEDIA
Get PDFGranular materials play an important role in a diverse set of applications, ranging from manufacturing to defense. Under compression, these materials exhibit highly heterogeneous kinematics and stresses. Their complex microstructures, stemming from diverse particle shapes, morphologies, and packings, pose challenges for predicting macroscopic behavior accurately. In this study, we investigate the influence of microstructure on macroscopic response under different loading conditions.
We first investigate granular microstructure under high-strain rate loading. A crucial aspect of this investigation involves quantifying the evolution of the 3D particle dynamics. Solving for the full, time-resolved particle positions can enable the identification of highly stressed regions, areas of increased plasticity, and pore collapse. To achieve this, we developed a ``quasi digital volume correlation'' approach to capture the complete 3D kinematics of granular materials undergoing high-strain rate loading. Using this tool, we explore the effects of particle morphology and packing on the heterogeneity of particle kinematics. The results provide insights into dynamic processes at the particle scale and will help inform continuum models.
We then investigate the behavior of complex granular microstructures subjected to quasi-static, small-strain loading. Under compression, these complex microstructures allow for the formation of force chains, in which columns of highly-loaded particles are supported by clusters of minimally-loaded particles. Understanding the interactions between these networks is important for better predicting macroscopic response. We propose a micromechanics model that explicitly considers both force chain structure and mesoscale interactions. This model connects micro and mesoscale phenomena to the continuum response.
We finally investigate the effects of evolving granular microstructures under quasi-static, steady-state shear loading. Under steady-state shear, granular materials experience periodic stress build-up and release at the continuum scale. To further understand this behavior, we analyze the evolution of distinct contact networks, tracking the flow of energy through them. We investigate the interplay between potential energy and shear stress and its role in driving system instabilities. Ultimately, linking the microstructural evolution with global stress fluctuations can enable a better understanding and prediction of local and global instabilities
Promoting Environmental Justice via Cumulative Approaches to Environmental Decision-Making
No full textCurrent approaches to environmental decision-making often fail to consider environmental exposures and risks in a holistic manner. In this work, we aim to address this issue by demonstrating and innovating upon approaches to cumulative risk assessment and cumulative impact assessment. In Aim 1, we developed a quantitative approach to consider non-cancer health risks beyond only the most sensitive health endpoint. Demonstrating this approach using air monitoring data from fenceline communities in Southeastern Pennsylvania, we found several potential health risks not identified by standard approaches. We also propose a risk management approach – shifting to a lower benchmark for hazard quotients and hazard indices from 1 to 0.1 in disadvantaged and marginalized communities – to account for increased vulnerability in these areas. In Aim 2, we developed a survey to characterize cumulative impacts in Southeastern Pennsylvania using a community-based participatory research approach. Our results highlighted community concerns and impacts that would not be captured in a standard risk assessment, demonstrating the importance of cumulative impact frameworks. We also provide recommendations for successful community-based participatory research partnerships, which are central to this approach. In Aim 3, we identified, compared and evaluated mapping tools used by governmental agencies to characterize cumulative impacts. We found high heterogeneity between methods and outputs of existing tools, highlighting the need for future validation studies. We developed an evaluation framework and recommendations to guide the development and/or refinement of mapping tools. Our work advances cumulative approaches that may be used in support of environmental policies that better protect public health and address environmental injustice
What do the inattentionally blind see? A signal detection approach to visual awareness
Get PDFWhat are the requirements for visual awareness? My dissertation explores this question by investigating inattentional blindness (IB) — one of the best-known paradigms in all of psychology, and a phenomenon of immense practical, theoretical, and popular interest. In IB, observers fail to report clearly visible stimuli when attention is otherwise engaged, most famously even missing a gorilla parading before their eyes. The standard interpretation of this phenomenon is that we have no conscious awareness of unattended stimuli. So interpreted, IB undermines common sense assumptions about our ability to perceive the world. However, the orthodox interpretation of IB relies on simply asking observers whether they noticed any additional stimulus and taking observers at their word when they say "no." In the largest-ever studies on IB (>25,000 individual participants), I show that 'inattentionally blind' subjects can accurately discriminate numerous features of the stimuli they fail to report, including color, shape, and location, suggesting they are not completely blind to the unattended stimuli. Furthermore, extending traditional IB paradigms to include stimulus-absent trials for the first time reveals that observers exhibit a significant and systematic tendency to under-report their awareness. Together these findings have consequences for our understanding of the relation between attention and awareness: They vindicate the common-sense idea that we are aware of things outside of what we attend to, cast doubt on leading attention-based theories of consciousness, and call into question the use of IB as a tool in the search for neural correlates of consciousness