Boston College

NSF Awards · FY 2024 · 2024-08

Norms are people's beliefs about what others commonly do or value, and they can encourage individuals to change their behaviors to act in accordance with these perceptions. For example, if people believe others are buying all-electric vehicles (EVs), it should encourage them to purchase an EV for their next automobile. However, norms do not always change people's behaviors, and this project examines the factors determining what leads norms to be more contagious. In particular, it considers the role of dynamic norms, which are beliefs about how people's behaviors or beliefs are changing across time. These trend perceptions (e.g., an increasing number of people are purchasing EV automobiles) may be especially important in responding to major societal challenges. The project examines what qualities of trends lead people to follow suit when they see others as changing (leading the trend to grow) versus what attributes of a trend lead it to fail to spread and merely fade away. For example, attributes such as seeing a trend as likely to be long-lived (rather than a fad) or as being part of a broader shared social cause should encourage people to conform to that trend. This project investigates important society trends affecting public health, sustainability, energy security, and social inequality by considering four attributes about trends that make them more likely to inspire people to adopt them: Longevity (will this trend last?), Universality (will this trend spread widely?), Common Cause (are people changing for a cause?), and Sufficiency (is more change needed for that cause?). Understanding how these conditions lead people to join social movements helps explain when trends spread or fade, improving the understanding of when society is more likely to change in response to societal challenges. The research uses correlational, experimental, and field work approaches with nonprofit partnerships. The findings can inform organizations and policy makers in promoting practices that increase energy independence and reduce societal discord. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2024-08

PROJECT SUMMARY About 1 in 4 Americans who use insulin report rationing their insulin to save money. Emerging adults living with type 1 diabetes (T1D) have worse glycemic outcomes than other age groups. During this developmental stage, young people are compelled to navigate healthcare and insurance for the first time independently, while also experiencing the highest rates of poverty and unemployment among adults. Notably, researchers in the cancer literature have begun to describe this objective financial burden and subjective financial distress of healthcare costs, collectively named financial toxicity. In the last 10 years, financial toxicity has been described, measured, and targeted as the focus of interventions in cancer research. It is timely to elucidate how emerging adults with T1D experience these financial and healthcare burdens, mirroring the understanding of financial toxicity in the cancer literature into diabetes research. Katherine Wentzell, PhD, PNP, BC-ADM is a pediatric nurse practitioner and early-career clinical researcher who will target this understudied area in T1D in her K23 proposal focused on emerging adults. In her recent doctoral and postdoctoral work, she developed a new measure of diabetes distress in emerging adults, which included an item about the worry about diabetes costs and this item was the most highly endorsed on the survey. This preliminary work underscored her interest in investigating the impact of financial stressors in emerging adults with T1D, especially those with suboptimal glycemic control. She has assembled a multidisciplinary mentorship team led by national experts in diabetes clinical and behavioral research, as well as advisors with focused methodological and cost-related expertise. This K23 career development proposal includes 3 specific aims incorporating mixed-methods research and culminating in a pilot randomized controlled trial. In Aim 1a, Dr. Wentzell will use semi-structured interviews to describe the experience of financial toxicity, health insurance access, and cost-coping behaviors in a diverse sample of emerging adults. In Aim 1b, she will utilize the innovative methodology of asynchronous online text- based focus groups to expand the understanding of cost related non-adherence and financial toxicity in emerging adults with T1D. In Aim 2, Dr. Wentzell will develop and validate a new measure of financial toxicity and explore relationships among social determinants of health, health insurance access, and psychological factors as they relate to objective financial burden, subjective financial distress, and glycemic outcomes in a diverse nationwide sample of emerging adults with T1D. Finally, building on the results in the prior aims, in Aim 3, she will develop, implement, and evaluate a pilot psychoeducational intervention to reduce subjective financial distress and cost related non-adherence in emerging adults with suboptimal glycemic control. Through the proposed career development award, Dr. Wentzell will acquire important skills in mixed-methods and intervention research to reach her goal of becoming an independent clinical investigator.

NSF Awards · FY 2024 · 2024-08

During the ice ages of the past few million years, ice sheets repeatedly grew southward from the Arctic. The ice sheet in North America advanced as far south as New York City during the most recent ice age, but little is known about its size before then. This project will determine if the ice sheet also reached New York during each of the past five ice ages using cave formations (speleothems) in the area. The findings will show how consistently (or not) ice sheets respond to drivers of climate change and improve estimates of how high sea levels rose during warm periods between ice ages. Given that ongoing ice sheet melt is projected to accelerate in our warming world, the real-world data generated in this research will provide timely information on how ice sheets and climate are linked. The most compelling findings will be delivered to the public through tours at a popular show cave and shared with the caving community through National Speleological Society print and online media. The scientists will participate in the NSS’s “Request a Speleoguest” program linking K-12 educators with cave experts, as well as develop an educational module, including caving trips, for a New York City charter school that serves primarily low-income students. This project will apply a well-known but overlooked approach to constraining the Laurentide Ice Sheet’s (LIS) southern limit during glacial maxima of the past 500 kyr: developing a speleothem growth chronology within the ice sheet’s footprint. 150 uranium-thorium ages will be measured on a large collection of speleothems from 17 caves in east-central New York State, only 100-200 km inboard of its Last Glacial Maximum (LGM) margin. This chronology can provide a binary proxy of ice cover through time – speleothem growth typically occurs when ice-free conditions permit liquid water charged with soil CO2 to percolate into a well-ventilated cave, whereas growth usually halts when an area is glacier covered. Stable isotope profiles will also be measured along speleothems to develop a long climate reconstruction. The results will help address four longstanding problems in paleoclimate. (1) Did the LIS advance to near its LGM extent every glaciation? (2) How are interglacial sea level markers affected by the size and timing of prior ice loading? (3) Were abrupt glacial climate events related to rerouting of freshwater runoff by an oscillating LIS margin in eastern North America? (4) How were orbital and millennial-scale climate change expressed in the mid latitudes, near the LIS and upwind of the North Atlantic? This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-08

This RAPID project is a field campaign to capture post-storm observations in three morphologically-distinct locations to better characterize storm-induced erosion and deposition across barrier islands from sequential storms. The investigators will leverage and complement a pre-storm dataset, which was collected one week prior to Tropical Storm Alberto along the central Texas Coast. Hurricane Beryl, the earliest Atlantic Basin Category 5 storm in recorded history, made landfall in Texas as a Category 1 cyclone, approximately two weeks after Tropical Storm Alberto. The pre-storm data presents a unique opportunity to tightly constrain the morphologic change due to two sequential, low-intensity tropical cycles. These morphologic changes leave critical signatures in the sedimentary record, which can be easily reworked by natural and anthropogenic disturbances. Therefore, rapid deployment and data collection are necessary to accurately capture and quantify sequential event forcings needed to improve morphodynamic and storm wave and surge models. The project provides research and training opportunities to women and underrepresented minorities in STEM and fosters partnerships between academia and industry. Field-based observations of coastal sedimentology and morphologic change during sequential storms will advance knowledge and predictive abilities by: 1) utilizing bedforms and sedimentary structures to constrain flow velocities, direction, transport stage, and duration of inundation; 2) evaluating compound change from sequential, low-intensity storm events; 3) providing calibration and validation data for morphodynamic and hydrodynamic models; and 4) developing volumetric assessments of coastal sediment transport which are necessary to calculate regional sediment budgets and assess coastal resilience. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-08

The central theme of this project is that certain classes of mathematical shapes can be understood better by analyzing other shapes that they approximate. For instance, a sphere with a very large radius, like the earth, approximates a flat plane from the perspective of a person standing upon it. Planar geometry then informs the study of spherical geometry. The particular shapes considered in this project are `hyperbolic manifolds', which have been among the most important objects in theoretical geometry for the past hundred years. To supplement the research component of the project, the PI will continue to develop inquiry-based learning (IBL) courses at Boston College, will revise and disseminate his online book `Geometry in 2 dimensions', and run learning workshops for early career mathematicians. In low dimensional geometry and topology, one often studies a sequence of Riemannian manifolds by passing to an appropriate `geometric limit' manifold. For instance, this technique is essential in Thurston's program to understand 3-dimensional manifolds via hyperbolic geometry, and in the proof of his Geometrization Conjecture by Perelman in 2003. This current project is centered on the structure and applications of geometric limits, especially in hyperbolic geometry. Specifically, the PI will study the global topology of the associated `space of all hyperbolic manifolds', continuing his previous work with Lazarovich-Leitner and Warakkagun, and will use geometric limits and their probabilistic cousins `Benjamini-Schramm limits' to study the relationship between the `rank' of a closed hyperbolic 3-manifold and its geometry, extending his previous work with Souto and Abert et al. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY N6-methyladenosine (m6A) is one of the most abundant chemical modifications in human messenger RNA (mRNA). m6A in mRNA is dynamically regulated by the effector proteins that install, remove, and specifically recognize m6A-modified transcripts, which are known as writers, erasers, and readers, respectively. Growing evidence has suggested the significant roles of m6A in cancers including acute myeloid leukemia, endometrial cancer, breast cancer, and glioblastoma. Dysregulations in m6A, its effector proteins, and related metabolites have been shown to significantly influence the development of tumors, drug resistance, prognosis, and the spread of cancer in various forms. However, understanding of the explicit roles of m6A in cancer biology remains incomplete. Current efforts on understanding epitranscriptomic regulations heavily rely on altering the expression of an effector protein, which typically generates global alterations to the modification levels on hundreds of mRNA substrates and perturbs all other molecular interactions involving the effector protein beyond their roles in regulating RNA modifications. With such convoluted results, it is challenging to deduce the explicit functions of m6A on specific genes. To identify key regulatory m6A-modified transcripts in cancers, tools that enable efficient and precise installation of m6A(s) at any one or multiple mRNAs of interest are highly desirable. One major challenge is that the existing m6A writer or methyltransferases suffer from slow turnover rates, dependence upon auxiliary proteins, and sequence biases of RNA substrates. Here we propose to develop a directed evolution platform to evolve RNA MTases with improved catalytic efficiency and reduced substrate sequence recognition biases. This directed evolution platform will leverage in vitro compartmentalization and m6A-specific endoribonucleases to achieve rapid enrichments of functional MTase variants from a diverse (1010) library. The evolved MTases will be further fused with RNA-targeting CRISPR-Cas systems to achieve site-specific installation of m6A with high efficiency and reduced off-target editing.

NSF Awards · FY 2024 · 2024-07

This project will determine when and how quickly the Cordilleran Ice Sheet in western Canada disappeared since the end of the last ice age, approximately 20 to 10 thousand years ago. It will create a 3-D reconstruction of the ice sheet’s collapse through geologic dating of rock samples collected from mountains across the region that record the lowering ice sheet surface and use computer models of the ice sheet shape to help ‘connect the dots’ between these datapoints. Because the Cordilleran Ice Sheet shared many similarities with the present-day Greenland Ice Sheet, this reconstruction will provide a key test for models used to simulate Greenland’s future decay – one of the largest and most uncertain sources of sea level rise. The project will build an international collaboration from the U.S., U.K., and Canada and train the next generation of scientists in holistic approaches to better understanding how ice sheets collapse. The team will contribute content to a popular website on glaciers targeted at the general public and teachers/students. A climate journalist will take part in fieldwork and potentially write a story. Projections of future sea level rise rely on ice sheet models that are highly tuned to the present day, limiting confidence in their ability to simulate the future. Recent advances in cosmogenic dating as well as ice sheet modeling and uncertainty quantification now make it feasible to use reconstructions of past ice sheet changes to test and improve coupled climate-ice sheet models. The deglaciation of the Cordilleran Ice Sheet is poorly constrained, yet this ice sheet offers great potential to constrain models due to its similarities to the southern Greenland Ice Sheet: mountainous, high mass accumulation, strong precipitation gradients, and marine/land terminating. The Cordilleran Ice Sheet is also thought to have played a key role in rapid sea level and climate changes during the last deglaciation, but evidence of this is limited. This project will produce the first 3-D reconstruction of Cordilleran Ice Sheet collapse. It will apply the "glacial dipstick" approach, generating 135 10Be ages along ~15 vertical transects. Using a Bayesian Uncertainty Quantification approach, these field data will be combined with Cordilleran Ice Sheet simulations from a complex yet efficient coupled climate-ice sheet model used for future projections. This will produce an ensemble of plausible reconstructions for the deglaciation of the Cordilleran Ice Sheet. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2024 · 2024-07

ABSTRACT Learning about and using environmental cues for safety is critical for survival and mental wellbeing. Current research on safety signals identifies the basolateral amygdala, insular cortex and infralimbic prefrontal cortex as important components of the neural circuits needed to process safety signals. These structures are anatomically interconnected and the proposed studies will be the first to test whether they work together in response to safety signals to mediate safety learning and fear inhibition. Prior mechanistic and descriptive electrophysiology experiments point to the amygdala and insula as key sites for safety learning but not necessarily for recall. Aim 1 will test the hypothesis that basolateral amygdala neurons that project to the insular cortex convey information about the safety signal and are necessary for safety learning. In contrast, the infralimbic cortex is responsive to already learned safety signals and is thought to be critical for behavioral inhibition during threat. Aim 2 will test the hypothesis that infralimbic neurons which receive input from the insular cortex are critical for fear inhibition by safety signals. The results will help complete our understanding of the neural mechanisms underlying safety learning and provide a basis for understanding abnormal safety related behavior in psychopathology.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY Globally, mental disorders are the second largest contributor to the burden of disease in adults. In settings disrupted by war and civil unrest, violence and loss contribute to significant unaddressed burden of mental disorders and family violence in adults with subsequent risks to children. In Rwanda the intergenerational mental health consequences of the 1994 Genocide against the Tutsi in Rwanda persist; recent studies found that 20% of the Rwandan population has one or more mental disorders with the highest rates observed in Genocide survivors. Sugira Muryango is an evidence-based, trauma-informed, family-based behavioral intervention to promote healthy family functioning, early childhood development and reduce family violence. In several trials, Sugira Muryango has led to improvements in parental mental health and child development outcomes including social and emotional development of children, improved caregiver mental health and reductions in family violence. To support scaling the intervention the University of Rwanda and other partners developed a Digital Dashboard tool that: (a) streamlines collection of data on evidence-based intervention quality and reach; (b) improves visibility and searchability of implementation data by region; (c) facilitates caregiver mental health and social services referrals and follow up; and (d) serves as a training platform with resources to enhance interventionist fidelity and competence. In the context of understanding important factors for scaling evidence-based interventions, the proposed research will investigate dashboard-supported delivery of Sugira Muryango in terms of its reach, efficiency, and cost effectiveness. The Hybrid Type 3 implementation-effectiveness study will collect outcomes measuring the program’s effectiveness, quality of program delivery, feasibility, and acceptability from program beneficiaries, the interventionists, their supervisors, and community stakeholders. The study will compare the trajectories of fidelity, competence, and self-efficacy between dashboard-supported delivery and standard delivery. The study will also include social network analysis to understand how the characteristics of networks comprised of supervisors and interventionists affect trajectories over time. Lastly, the study will investigate the impact of dashboard-supported delivery by comparing the difference in child and caregiver mental health outcomes with standard delivery. These data will be used to analyze cost-effectiveness and return on investment of the intervention as delivered with and without the Dashboard. The results of the proposed research will identify scalable pathways to accelerate integration of technology and evidence-based mental health services into policy and practice in Rwanda.

NSF Awards · FY 2024 · 2024-06

Non-technical Abstract: Polysaccharides are polymers of sugar molecules. Examples include cellulose found in cotton and wood, amylose in the starch found in bread and rice, and chitins found in the exoskeleton of insects. Today, polysaccharides are preferred renewable materials for many applications, such as packaging, healthcare, personal care, and agriculture. However, polysaccharides found in nature can vary greatly in structure and purity, making them difficult to study and use effectively. The structures and properties of synthetic polysaccharides could be precisely controlled, but existing methods for synthesizing polysaccharides are often impractical for large-scale production. The goal of this research project is to find a new way to design and make a variety of polysaccharides with precisely controlled structures from natural sugars. In addition, non-sugar units will be blended with sugar units in these polymers to match and even surpass the properties of natural polysaccharides. This project will also establish a meeting called Massachusetts-Missouri Macro-Materials Meeting (5M). This meeting will promote the communication and collaboration of polymer scientists in the states of Massachusetts and Missouri and the nearby regions, and encourage college students from diverse backgrounds to pursue careers in STEM. Technical Abstract: The overall goal of the proposed research is to develop novel polysaccharide-based soft materials. Toward this goal, novel approaches to precision polysaccharides through living cationic ring-opening polymerization (CROP) of anhydrosugars will be devised. Precision polysaccharides are synthetic polysaccharides consisting of native glycosidic linkage and well-controlled molecular weight, dispersity, side-chain groups, and chain-end groups. Living CROP of anhydrosugars will be used to generate precision polysaccharide homopolymers with various monosaccharide repeating units, side-chain groups, and molecular weights to establish a comprehensive structure-property understanding. Detailed reactivity studies in the copolymerization of the anhydrosugar monomers and non-carbohydrate monomers will lead to a novel class of statistical copolymers. The knowledge gained through these fundamental studies will enable the additive manufacturing of these materials, amplifying their molecular-scale structural features to the macroscopic level. The nano-to-macroscale understanding of the structure-property relationship will further advance the development of even more sophisticated block copolysaccharide elastomers and mixed graft copolymers with polysaccharide branches. As part of this project, a new Massachusetts-Missouri Macro-Materials Meeting (5M) will be developed to provide a platform to promote research, communication, and STEM education among researchers and college youths. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-06

Summary Fast rounds of host cell invasion and intracellular replication are responsible for tissue lesions caused by the tachyzoite form of the opportunistic human parasite Toxoplasma gondii. Underlying the lytic cycle is a parasite-specific replication mechanism, which forms two new daughter cells in the cytosol of the mother (endodyogeny). The process is fundamentally different from cell division of the host and relies on a specialized cytoskeleton, called Inner Membrane Complex (IMC), which is deposited on 22 subpellicular microtubules (SPMTs). This unique cytoskeleton is involved in all aspects of the lytic cycle and acts as an essential scaffold during the division process. The current working model suggests SPMTs nucleate from the apical polar ring (APR), a presumed secondary microtubule-organizing center (MTOC) in the parasite. However, very limited experimental data exists that corroborates this. Furthermore, how SPMTs connect to the APR early in division is also unknown. Several factors have recently been identified that facilitate the association of SPMTs and APR later in the budding cycle, but phenotypic consequences of protein depletion indicate that none impact the early division steps. This indicates that currently the early events of parasite budding are incompletely understood. To fill this void, we started to interrogate the budding cycle using iterative expansion microscopy (ExM) and identified an intriguing five-fold assembly of the nascent SPMTs (nSPMTs) at the onset of division. Our data indicate that nSPMTs are organized into five “sheets” –consisting of approximately four individual nSPMTs– grouped around the nascent APR. This suggests that nucleation unfolds in distinct areas and a separate event, later in budding, arranges the even spacing of SPMTs around the APR as seen in mature parasites. To probe further into the nucleation mechanism we localized γ-Tubulin to the forming APR, specifically at the onset of division. Its presence there is short-lived, indicating a function specifically tailored to the early daughter scaffold. We hypothesize that γ-Tubulin and its associated complex (γ-TuC) play a pivotal role in the early stages of division. We will test this under two specific Aims. Aim 1 will establish the budding-related functions of γ-TuC. We will study this by conditional depletion of γ-TuC components in combination with iterative ExM. Under Aim 2 we will employ reciprocal proximity biotinylation in combination with chemical perturbation to specifically reveal the molecular make-up of γ-TuC at the forming cytoskeleton. This will allow us to gain a more complete understanding of its molecular functions. Together, our findings will establish the role of γ- TuC in parasite budding, which may also be relevant for other apicomplexan parasites equipped with a similar cytoskeleton.

NIH Research Projects · FY 2026 · 2024-01

PROJECT SUMMARY/ABSTRACT In mammals, insulin primarily regulates metabolism while insulin-like growth factor-1 (IGF-1) stimulates growth, proliferation and differentiation. Aberrant production of IGF-1 is connected with different human diseases including growth disorders such as Laron syndrome, acromegaly and Graves' orbitopathy as well as thyroid eye disease (TED) and the early stages of diabetic nephropathy. In addition, circulating levels of IGF-1 are increased in cancer patients and IGF-1 receptor (IGF1R) expression is upregulated in various tumor types. Although the IGF1R system plays a key role in tumor progression and has been one of the most intensively investigated molecular targets in cancer research, previous clinical attempts to develop IGF1R inhibitors have largely failed. Thus, there is a critical knowledge gap regarding the underlying mechanisms of IGF1R inhibition and an urgent need to develop novel IGF1R inhibitors. The data generated through my K01 grant has expanded the family of insulin/IGF-like hormones and provided us a new tool to probe this complex system: viral insulin/IGF-1-like peptides (VILPs). Previously, we chemically synthesized these VILPs and characterized their function on the insulin receptor (IR)/IGF1R system using in vitro and in vivo assays. While most of the VILPs are natural agonists of the IR and IGF1R, we showed that two VILPs in Mandarin fish ranavirus (MFRV) and Lymphocystis disease virus-1 (LCDV1) are highly specific and potent antagonists of the IGF1R. This discovery has opened up new avenues for understanding and studying IGF1R inhibition. The overarching goal of this proposal is to examine unique antagonist effects of MFRV and LCDV VILPs on the IGF1R to elucidate the underlying structural and molecular mechanisms of the IGF1R inhibition. Our central hypothesis is that the VILPs will inhibit IGF1R signaling and IGF-1 related proliferation function via their unique interaction with the IGF1R, differentially regulating post-receptor signaling pathways and IGF1R gene expression. We will test this hypothesis based on two independent Aims. In Aim 1, we will test the hypothesis that VILPs engage with human IGF1R in a unique way, recruit different substrates to the receptor and modify post-receptor signaling while directly regulating IGF1R gene expression. We expect to determine the molecular and structural mechanisms of the hIGF1R antagonism in vitro. In Aim 2, we will test the hypothesis that VILPs will specifically inhibit IGF1R signaling in vivo without affecting IR signaling and decrease IGF-1 mediated growth without affecting glucose metabolism. These findings will define the effects of VILP-mediated IGF1R inhibition using two in vivo models of IGF-1 mediated growth and IGF-1 mediated tumor progression. This proposal is built on the conceptual innovation based on our exciting discovery of the VILPs and their unique effects on IGF1R. We propose using cutting-edge techniques and if proven right, these studies will transform our understanding of the IGF1R inhibition and function as a proof-of-principle for the introduction of peptide-based inhibitors of the IGF1R into the framework of human disease research.

NIH Research Projects · FY 2026 · 2024-01

Streamlining PPI Inhibitor Discovery via Chemically Enhanced Phage Display Project Summary Protein-protein interactions (PPIs) are increasingly recognized as rewarding targets against which powerful therapeutic drugs can be devised. This is perhaps best demonstrated by the remarkable success of the series of anti-PD-1/PD-L1 antibody drugs developed to treat cancer. Despite the excitement, antibody-based drugs do have a few limitations, including modest stability, lack of oral availability, poor tissue penetration and inability to reach intracellular targets. Nevertheless, small molecule based PPI inhibitors remain scarce as large PPI interfaces cannot be efficiently blocked by small molecule drugs. The shortcomings of these two major drug modalities towards PPI inhibition rekindled people’s interest in peptides as an alternative modality. Peptides, as a quintessential example of medium-sized molecules, would be able to forge large enough molecular contact to block a PPI interface. On the other hand, they hold promise to overcome the limitations of antibody drugs, particularly in terms of oral availability. The enthusiasm in peptide drugs was further fueled by the advent of genetically encoded screening platforms such as phage display, which enables rapid screening of peptide libraries. However, phage display often fails to reveal PPI inhibitors of desired potency, presumably due to the overly simplistic structures of natural peptides in contrast to peptide natural product-based drugs. Over the past few years, our group have made a number of exciting advances towards expanding the chemical space of phage display libraries. First, we have developed novel warheads that elicit reversible covalent binding of amines such as a lysine side chain. Second, we have successfully constructed covalent binding phage libraries and demonstrated their utility in PPI inhibitor discovery. Third, we have developed highly efficient chemistries for phage modification to give backbone rigidified peptide macrocycle libraries. These advances pave the road for the further exploration of phage libraries of complex structured peptides. With this MIRA application, we seek to develop novel phage libraries that display various covalent warheads and/or backbone rigidifying elements. These phage libraries will be assessed for PPI inhibitor discovery against a panel of model proteins as well as proteins that enable bacterial immune evasion or confer antibiotic resistance. Our proposed research will allow, for the first time, pharmacologic interrogation of host-pathogen PPIs as potential targets of novel antibacterials. Importantly, the proposed work will yield a powerful platform for discovering non-antibody based PPI inhibitors, which will have broad impact far beyond the scope of this proposal.

NIH Research Projects · FY 2025 · 2023-12

Project Summary Streptococcus pneumoniae is a leading cause of pneumonia, acute otitis media (ear infection), and meningitis in the United States. S. pneumoniae remains an important pathogen despite a vaccine and effective antibiotic treatments due to increasing levels of antibiotic resistance and vaccine evasion through serotype switching. Virulence in S. pneumoniae is mediated by a complex gene regulatory program that is only partially understood. In many bacteria, trans-acting small non-coding RNAs (sRNAs) play key roles in regulating stress and virulence responses. While many sRNAs have been identified in S. pneumoniae via high-throughput sequencing studies, biological function has been assigned to only a few. The goal of this exploratory proposal is to identify the mRNA targets for sRNA candidates in S. pneumoniae, focusing specifically on those implicated in mediating virulence. We have two aims to reach this goal: First, we will determine the mRNA targets for a set of prioritized sRNA candidates implicated in S. pneumoniae virulence during mouse infections. Second, we will characterize the entire S. pneumoniae sRNA:mRNA interaction network. To achieve the first aim, we will use MS2-afinity purification coupled with RNA sequencing (MAPS) to identify mRNA targets for a set of prioritized sRNAs associated with fitness defects in mouse infections. MAPS tags each sRNA individually to allow specific capture of sRNA targets, but allows unbiased identification of potential mRNA partners via high-throughput sequencing of the captured RNAs. This approach will be combined with computational tools that predict the targets of sRNAs using thermodynamic properties. A set of 5- 10 of the most promising mRNA targets identified from the combined approaches will be assessed using reporter gene assays to validate the sRNA impact on gene expression. To achieve the second aim, we will use RIL-seq, a technique which captures mRNA:sRNA pairing through crosslinking followed by ligation. Subsequent sequencing identifies chimeric reads corresponding two interacting RNAs. To enrich for sRNA:mRNA pairs, a FLAG-tagged RNA-binding protein partner to immunoprecipitated the sRNAs. In S. pneumoniae, which lacks an RNA chaperone, we will use Cbf1, an exonuclease shown to process sRNAs, to enrich our population. Taken together, our two aims will identify mRNA targets for sRNA candidates associated with virulence, and move the field from cataloging sRNA presence toward identification of sRNA biological function, and thus therapeutic intervention.

NIH Research Projects · FY 2024 · 2023-09

Summary Toxoplasma gondii is an obligate intracellular apicomplexan parasite causing severe opportunistic infections. Current drugs are prone to induce hypersensitivity, especially upon long-term use. Infection comprises a short, acute stage (tachyzoite) followed by a dormant stage (bradyzoites in tissue cysts) for the life of the host. However, an impaired or suppressed immune response (e.g., AIDS, organ transplant, cancer treatment) can lead to reactivation of a dormant infection that was acquired years ago, leading to clinical toxoplasmosis. Interference with the tachyzoite-bradyzoite interconversion is an attractive target for novel therapeutic strategies. A key factor in stage interconversion is the ability to respond to stress: the immune response ‘stress’ maintains the bradyzoite stage, but if it wanes, the parasite defaults back to the acute stage. Reprogramming toward the bradyzoite is facilitated by the competitive interplay of about 10 transcription factors (TFs) balancing sequential, cooperative, and opposing roles. The research team recently discovered that the TF set associated with bradyzoite differentiation overlaps by 2/3 with the TFs expressed in parasites exposed to the extracellular (e.c.) environment. This provided the first glimpse of how the stress response is integrated into the transcriptional program leading to the bradyzoite. Indeed, the transcriptome of e.c. and bradyzoite parasites shares many genes, which positions the extracellular stage in between tachyzoites and bradyzoites. Here, the stress-related transcriptional program will be further dissected by extending on this observation with innovative CUT&RUN, single cell expression profiling (scRNA-seq), and the application of a novel in vitro generated myotube bradyzoite differentiation system. Excitingly, this myotube system demonstrated that spontaneous bradyzoite differentiation occurs in this cell type, but to reach and maintain a mature bradyzoite state, an exogenous, alkaline stress needs to be applied. Hence, this provides the perfect platform to dissect the contribution of stress-related transcriptional regulation to bradyzoite maturation. In short, the transcriptional network of stress will be dissected by 1. identifying the genes controlled by the 4-6 TFs shared between e.c. stress and bradyzoite conversion through CUT&RUN experiments; 2. scRNA-seq of mixed cell populations representing the transcriptional transitions of extracellular stress over the span of 6 hrs, and myotube-induced bradyzoite differentiation with and without alkaline stress. An advanced computational pipeline will be established to model the transitional programs that will permit answers to several open questions, such as: is there indeed a two-step bradyzoite differentiation pathway, and what are the genes driving these?; is the myotube seen as a stress by the parasites or not?; is there a specific stage in the cell cycle when bradyzoite differentiation occurs (a G2-like cell cycle stage and the late G1 restriction-checkpoint have been proposed)? In addition, comparative mapping of stress responses under different conditions will provide insights in how stress is integrated at the distinct parasite stages to modulate the stage-specific transcriptional responses.

NIH Research Projects · FY 2025 · 2023-09

INVESTIGATE SEQUENCE SPECIFICITY IN THE BIOSYNTHESIS AND RECOGNITION OF RNA CHEMICAL MODIFICATIONS PROJECT SUMMARY Chemical modifications are prevalent in the cellular RNA across all domains of life; they expand the chemical space beyond the four natural building blocks of RNA, modulate folding, intermolecular interactions involving RNA, and regulate gene expression. Growing evidence shows that several RNA chemical modifications can be reversed by endogenous enzymes and can respond to external cues, including metabolic signaling, nutrient starvation, oxidative stress, and temperature change. Interestingly, many proteins known to directly or indirectly regulate RNA chemical modifications are found to be dysregulated in physiological defects or diseases, forming the basis of many exciting hypotheses to discover the role of the epitranscriptome in gene expression regulation. While our understanding and therapeutic exploitation of epitranscriptome-based gene expression control continue to expand, the molecular mechanisms that govern this regulation remain poorly understood. A critical question in the epitranscriptome field is the sequence specificity of various RNA modifications: how they are installed on specific sequence locations and how they regulate specific protein-RNA recognition. Studying the sequence contexts of chemically modified endogenous RNA has been technically challenging. With recent advances in high-throughput sequencing-based technologies, we can now map and quantify only a handful of RNA chemical modifications (out of over 150 types) in their native sequence contexts inside cells. The pilot mapping studies revealed conserved sequence elements associated with the occurrence of specific modifications across different domains of life. That such conserved occurrence of modifications, rather than being randomly distributed, strongly suggests the involvement of dedicated endogenous machinery that regulates modifications with high specificity. However, we do not understand why and how the modifications are installed at specific locations and regulate biology, most likely in a sequence-dependent manner. To address this knowledge gap, we need methods to detect RNA modifications confidently within sequence contexts that offer high accuracy and throughput. Here we propose a program focusing on developing such methods and performing systematic biochemical characterization of the sequence specificity of effector proteins by combining in vitro high-throughput assay and in cellulo massive parallel reporter assay approaches. Inspired by recent findings that modification reader proteins may recognize more than one chemical modification, we aim to revisit the molecular recognition mechanism of the most heavily modified RNA – transfer RNAs in human cells. By developing more advanced detection tools in mapping RNA chemical modifications in biological RNA and designed oligonucleotide libraries modified in vitro or in cellular reporter assays, we will elucidate the fundamental biochemical properties of the critical regulators of the epitranscriptome with unprecedented efficiency and comprehensiveness, leading to a better understanding of RNA regulation, and new opportunities to exploit and control the epitranscriptome.

NIH Research Projects · FY 2025 · 2023-08

Project Summary/Abstract Several cardiac diseases involve the progressive or acute loss of cardiomyocytes, which are replaced by fibrotic tissue. Cardiac fibrosis is one of the leading factors in the pathology of heart failure, a progressive disease that affects millions of people every year. Despite its recognized importance, there are no effective therapies to prevent the progression of cardiac fibrosis. Recent findings suggest that naturally occurring genetic variants protect certain individuals against the adverse changes triggered after cardiac injury, which translates into re- duced cardiac fibrosis. One of the genes that modifies the progression of disease is the cardiomyocyte-specific kinase Tnni3k. Mutations that abolish Tnni3k confer resistance to injury, and high Tnni3k levels are associated with rapid functional decline and pathological remodeling. Tnni3k is an understudied kinase, and its downstream targets and specific mechanisms by which it defines injury outcome are unknown. Our goal in this project is to identify the mechanisms linking Tnni3k levels to cardiac fibrosis. In preliminary experiments using the zebrafish as a model, we found that high levels of Tnni3k induce fibrosis deposition shortly after cardiac injury. In contrast to their wild-type siblings, animals overexpressing Tnni3k showed impaired fibrotic regression, while a newly generated tnni3k mutant exhibits minimal fibrosis after injury. Transcriptional profiling revealed that high levels of Tnni3k correlate with an exacerbated inflammatory response, markers of T-cell infiltration, and activation of all the components of the inflammasome, which are all landmarks of cardiomyocyte-induced inflammation. We also identified a potential downstream target, itih5, which has been previously reported to play a role in extracel- lular matrix stabilization in the skin. Based on our preliminary results, our central hypothesis is that Tnni3k plays a previously unappreciated role in cardiac fibrosis via modulation of inflammation, and that Itih5 is a central mediator of these effects. We will test our hypothesis in three integrative aims. In Aim 1, we will determine the role of inflammation in the development of fibrosis in response to high levels of Tnni3k. We will exploit a collection of immunocompromised zebrafish to test the contribution of specific immune populations to this excessive fibrotic response. Additionally, we will use a new cardiomyocyte specific Cas9 line to identify genes required for trigger- ing inflammation in response to high Tnni3k levels. In Aim 2, we will determine the effects of modulating Tnni3k levels pre- and post-injury on cardiac fibrosis and inflammation. We will use a new Tnni3kSWITCH line generated by our lab that will allow us to “turn off” the overexpression of Tnni3k at different times. In Aim 3, we will identify molecular regulators of scar remodeling downstream of Tnni3k. We will start by analyzing how Itih5 regulates fibrosis regression using new gain and loss of function models generated by our laboratory for this application. Collectively, these studies will establish Tnni3k and Itih5 as regulators of cardiac inflammation and fibrosis in zebrafish. We anticipate that this basic knowledge will serve as the springboard for rapid discovery of new targets to treat cardiac fibrosis in the injured heart.

NIH Research Projects · FY 2025 · 2023-08

Despite the availability of highly effective biomedical prevention and treatment interventions for infectious diseases, their integration into public health programming has resulted in varied levels of health benefit across different settings. While improving outcomes remains a cornerstone of public health, there is a critical need for a scientifically rigorous, evidence-informed tool that can assess the operational capability of public health efforts. Such an instrument would support decision-makers in proactively identifying implementation challenges, aligning local strengths and gaps with context-specific needs, and optimizing the allocation of resources to improve consistency in health results. This project addresses that need by developing and evaluating the HEART Tool, a novel approach to assessing public health program capability. The study will: (1) apply structured, mixed methods to define and organize capability into measurable domains; (2) develop and test the content and format of the HEART tool, including preliminary psychometric validation; and (3) pilot and refine HEART across multiple public health settings. The anticipated outcome is a validated, pragmatic measure that can be used in both community- based and healthcare environments to guide planning and improve implementation outcomes. The principal investigator brings the necessary expertise to lead this work, supported by an interdisciplinary team with backgrounds in infectious disease prevention, measurement development, and real-world implementation. This proposal aligns with the New Innovator Award’s goals to advance transformative, conceptually novel, and scientifically promising approaches to major challenges in population health.

NIH Research Projects · FY 2025 · 2023-08

Summary Nuclear movement is evolutionarily conserved throughout eukaryotes, a testament to the fundamentally important nature of this process. The importance of this process is most evident in syncytial muscle cells, which move their nuclei to maximize the distance between each nucleus and its neighbors, a process thought to establish a series of independent myodomains. Furthermore, mispositioned nuclei in muscle cells are prevalent in muscle disease. In recent years, dozens of proteins have been implicated in the movement and spacing of nuclei, but their mechanisms of action, and the consequences of nuclear spacing, remain elusive. The goal of the proposed research is to fill this critical gap in knowledge. Specifically, we will define the features of the microtubule cytoskeleton that are critical for both moving nuclei to establish the spacing and anchor nuclei to maintain the spacing. Only recently have the molecular, physical, and imaging tools emerged to make it possible to address these mechanistic questions in vivo. In the proposed research we will generate and test mutant proteins that target the microtubule specific functions of pleitropic proteins to isolate the specific contribution of the microtubule interactions. We will then apply our recently developed analyses of nuclear movement and microtubule organization combined with classical genetic approaches to determine the genetic and molecular mechanisms by which these factors move and anchor nuclei during muscle development. Within this work we will test whether two emergent properties of the microtubule cytoskeleton, branching and sliding contribute to nuclear spacing in muscle. Finally, we will directly tie these data to disease pathogenesis by determining how dystrophin, the gene mutated in the most common and debilitating muscle disease contributes to these processes. Successful completion of these aims will provide the first mechanistic understanding of nuclear movement in an in-tact developing muscle cell making it possible to manipulate nuclear spacing to understand how the position of the nucleus impacts its function.

NIH Research Projects · FY 2026 · 2023-05

Project Summary Tuberculosis (TB) remains one of the leading infectious disease killers globally despite the availability of robust diagnostics, effective prevention, and treatment. Poor implementation of comprehensive TB programs and HIV infection remain drivers of ongoing high TB rates in high burden countries such as South Africa. In South Africa there are many losses in the TB care cascade; an estimated 95% of individuals with TB access evaluation, yet only 82% are diagnosed, 70% initiate treatment, and 53% successfully complete treatment. However, it is also imperative to also screen and treat subclinical TB infection to lessen the vast reservoir of people at risk of progressing to TB disease, especially recent contacts of TB patients and people living with HIV (PLH). Using implementation science methods and building on the success of the improvements in the HIV care cascade “90-90-90” targets, our team has recently piloted two TB care cascades for drug-resistant and drug-sensitive TB as well as piloted a TB prevention program including home visits to over 304 families, screening 922 household contacts of patients with TB. This R01 award will adapt the Systems Analysis and Improvement Approach (SAIA), an evidence-based implementation science strategy combining systems engineering tools into a clinic-level package for TB (SAIA- TB), expanding upon successful SAIA models trialed across a range of clinical settings in sub-Saharan Africa and the USA, and leveraging the PI’s preliminary TB cascade analysis data in South Africa. SAIA-TB will evaluate six comprehensive TB indicators (screening, evaluation, diagnosis, linkage to care, treatment, and TB-free survival) to aid frontline healthcare workers and managers to optimize cascade performance through the use of a TB cascade analysis tool, process flow mapping, and continuous quality improvement cycles. Our specific aims are to: (1) Evaluate the effectiveness of SAIA-TB on cascade optimization for patients with TB and high-risk contacts (specifically PLH). We will use a stepped-wedge crossover trial to evaluate the impact of SAIA-TB on comprehensive TB care in 12 rural clinics. We hypothesize that SAIA-TB implementation will lead to a 20% increase in TB screening and TB preventive therapy or TB disease treatment initiation during the 2-year intervention period. (2) Determine the drivers of SAIA-TB implementation variability across clinics. The implementation process will be described using focus group discussions and key informant interviews with clinic staff, analyzed using the consolidated framework for implementation research, with additional data gathered from study logs to describe fidelity to SAIA-TB. (3) Assess the acceptability of comprehensive TB care among patients accessing care at clinics implementing SAIA-TB at each step of the TB cascade. We will use the theoretical framework for acceptability and the socioecological model to define acceptability and compare individual-, family- and system-level barriers and facilitators to completing TB cascade steps among patients with and without HIV infection.

NIH Research Projects · FY 2025 · 2023-01

PROJECT SUMMARY Autism spectrum disorder (ASD) currently affects 1 in 59 children in the United States, 80% of whom are male, and is characterized primarily by impaired social interaction/communication. Prenatal exposure to air pollution has been implicated in the etiology of ASD, as well as many other neuropsychiatric disorders. However, the mechanisms by which air pollution alters the development of social circuits in the brain remains unknown. Importantly, there are large social disparities in environmental toxin exposure whereby marginalized communities bear the greatest burden of exposure. Using a novel mouse model that combines an environmental toxin (diesel exhaust particles; DEP) with an ethologically relevant maternal stressor (resource deprivation; MS), our preliminary data show that these exposures in combination, but neither alone, induce robust deficits in social interaction in male, but not female offspring. This is line with a model in which maternal psychosocial stress unmasks vulnerability to environmental toxins in offspring. ASD is increasingly recognized as a whole-body disorder. Gastrointestinal symptoms and changes in the composition of the gut microbiome are present in more than 50% of individuals with ASD. Studies using animal models suggest a causal link between the gut microbiome and social behavior, but this has not been studied in the context of environmental toxins. During the K99 phase of this proposal, in Aim 1, I propose to further my training in the analysis of the gut microbiome to ask whether cross-fostering of DEP/MS pups at birth can prevent shifts in the gut microbiome (assessed using metagenomic sequencing). The dopamine system supports social interaction, is sensitive to microbial signaling, and my preliminary data suggests is down-regulated following DEP/MS exposure. Thus, in Aim 2, I propose to learn in vivo optogenetic techniques to test whether activation of the mesolimbic dopamine reward pathway is sufficient to restore social behavior following DEP/MS. During the R00 phase, in Aim 3, I will use the techniques acquired during the K99 phase to determine whether changes in the gut microbiome are responsible for changes in social behavior and dopamine signaling in DEP/MS offspring. Moreover, I will use the preliminary data gathered in Aim 1 to ask what potential metabolites or molecular mechanisms might be altered following DEP/MS. Finally, I will ask whether microglia, the resident immune cells of the brain, play a key role in mediating these microbiome-driven changes. Together, these experiments will elucidate the ways in which pollutants and stress synergize to produce dysregulation of the gut-brain axis and deficits in social behavior. This proposal will significantly advance my career development by providing me with new training in cutting-edge techniques such as in vivo optogenetics and metagenomic sequencing. Thus, it will help me to establish my own independent line of work and the preliminary data obtained herein will serve as a foundation for future R01 funding.

NIH Research Projects · FY 2024 · 2022-09

Project Summary Latinxs, particularly those with mental illness, are at higher risk of COVID-19 infection, and associated morbidity and mortality, and yet have lower rates of vaccination, than non-Latinx whites. This pattern is not unique to COVID-19; it has been observed for other infectious diseases, including seasonal influenza. Vaccine hesitancy, understood as a delay in the acceptance of vaccination despite availability of vaccination services, is the primary roadblock for COVID-19 and influenza vaccination among Latinxs. Theoretical frameworks endorsed by the SAGE working group on vaccine hesitancy, and prior research, illustrate that interventions to reduce vaccine hesitancy and increase vaccine uptake in Latinxs should adopt strategies that: increase vaccine confidence and convenience; reduce vaccine complacency; and respond to contextual, individual and vaccine-related factors driving hesitancy, which include but are not limited to the social determinants of health and structural racism. While a variety of strategies have been developed to address vaccine hesitancy in priority populations, the potential role of behavioral health in community-based integrated health care settings has been overlooked. Yet behavioral health, particularly within federally qualified health centers (FQHCs) which target social determinants of health, may be an ideal setting to reach Latinxs, and other priority populations with mental illness, to address vaccine hesitancy and promote vaccine uptake. In collaboration with East Boston Neighborhood Health Center (EBNHC), the largest FQHC of Massachusetts, the proposed study will evaluate a novel Motivational Interviewing (MI) behavioral intervention to reduce vaccine hesitancy and increase COVID-19 and influenza vaccine uptake in Latinx adults with mental illness. Key to the intervention is that the proposed MI protocol explicitly acknowledges cultural values that are central to the Latinx population and that impact their interactions with health care providers. Additionally, the intervention has been specifically designed to be feasible and readily implemented in community-based settings, and to be sustainable in the long-term regardless of how the rapidly changing COVID-19 vaccination landscape evolves. To rigorously evaluate the intervention, we will conduct a pragmatic multiple-period cluster-randomized crossover trial within four BH programs at EBNHC; key to this design is that each program serves as its own control and that the multiple switches enhance statistical power. To our knowledge, this will be the first study to rigorously examine the potential role of BH providers in increasing vaccine uptake among Latinx adults with mental illness, a particularly vulnerable population. Key to the anticipated impact is the partnership between the academia-based research team and colleagues at EBNHC which, in turn, will support the rapid translation of evidence into practice together with a model for sustainable collaboration and national scaleup.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT Tissues in a developing (or regenerating) appendage must correctly interpret their location in biological space, and use this positional information to inform size, pattern and shape during outgrowth. Relative changes in how cells interpret their positions during development can lead to debilitating changes in appendage phenotype, including limb malformations. Further, the ability to regenerate requires that tissues remember or reinterpret positional identity, then re-deploy this information to guide regrowth. Nonetheless, despite incredible relevance to both basic biology and biomedicine, it remains poorly understood how spatial context regulates the local morphogenetic processes which sculpt the pattern and shape of growing organs. Understanding the nature of positional identity in vertebrate appendages can further efforts to prevent, diagnose and treat congenital limb disorders, and will be necessary for development of advanced regenerative therapies. Zebrafish fins are a powerful system for studying mechanisms of growth and regeneration, and the caudal (tail) fin possesses an elegant, simple-yet-informative structure. After amputation or removal of any portion of the organ, fins regenerate rapidly to reproduce the original size, patterning and shape. Long- and short-finned mu- tants have served as crucial tools in decades of important progress towards the mechanisms regulating rela- tive fin size. Fin length phenotypes preserve the proportional patterning and overall shape of the fin structure— length is the only aspect of morphology that is altered. Indeed, before now, there have not been experimental models to disrupt fin ray patterning or the forked shape of the fin, and this lack of experimental tools means that essentially nothing is known about how pattern and shape are established or remembered. In this proposal, researchers introduce novel phenotypes in which patterning and shape are decoupled from size in the fin; these tools will be used to identify pathways and cellular processes underlying positional identity and the morphogenesis of form. The team will initially focus on mechanisms of skeletal patterning along the proximo-distal axis of fin rays, using the discovery that thyroid hormone regulates relative ray polarity. The re- searchers next ask how identity is imprinted across the medio-lateral axis. The team has developed a system in which the adult fin never develops a central cleft, and grows into a triangular rather than a forked shape. This phenotype will be used to test a model in which larval Shh expression regulates relative morphogenetic behaviors across the fin fold to pre-pattern the eventual forked shape of the organ. Researchers will explicitly identify the cell states that constitute modules of positional identity regulating size, patterning and shape—the three essential characteristics of overall fin morphology. In all, the proposed research will open fresh horizons for the broader field, leveraging new paradigms by which different aspects of positional identity can inform morphogenesis. These advances are expected to contribute foundational knowledge relevant in developing clinical interventions for congenital disorders, and critical in laying the groundwork for regenerative medicine.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY The details we bring to mind about past positive and negative events can have important implications for our mental wellbeing, affecting how we see ourselves and maintain relationships with others. Do we vividly remember an argument with a friend, or the heartfelt apology that followed? Do we remember the feeling of accomplishment after giving a talk, or our struggle to answer an audience member’s question? The details we bring to mind also can affect our decision-making, with consequences for our social networks and career success: Will we call that friend again? Will we agree to give a talk at an upcoming meeting? There are fascinating examples that suggest that what emotional details we remember from past events may vary, in part, with a person’s age. Older age is associated with a greater use of positive (vs. negative) words in descriptions of past events (Pennebaker & Stone, 2003; Ford et al., 2016), and with a greater reported focus on positive aspects of otherwise challenging situations (Ford et al., 2018a, b). Yet we understand little about why such differences arise, and the answer is likely to have implications for understanding how cognition-emotion links differ across the adult lifespan and how adults of various ages achieve mental wellbeing. The first aims of this research are to understand these differences upon initial retrieval, focusing on memory phenomenology (Aim 1) and neural representations (Aim 2). Using multivoxel pattern analysis (MVPA), we examine two types of recapitulation: trial-specific (tied to each specific encoded event) and valence-generalized (shared across stimuli of a particular valence category). We hypothesize that, with older age, memory representations will have more valence-generalized vs. trial-specific recapitulation, and this age-related difference will be most pronounced for memories of positive content. We anticipate this will be reflected in positive memories feeling subjectively vivid to older adults, while lacking in specific detail. A key feature of episodic memory is that it is not a static representation. The details we remember now are not necessarily the details we will remember later, though the way we represent a memory now can tip the scales, making some details more likely to come to mind later and others more likely to be omitted. For emotional memories, our recent research and preliminary data suggest that retrieval at one time-point may trigger the start of what could colloquially be thought of as a “virtuous-memory-cycle”, with positive details emphasized and negative details de-emphasized, or the opposite, a “vicious-memory-cycle.” Critically, we hypothesize that older age increases the likelihood of a “virtuous-memory-cycle.” We propose that age-related differences in memory representations make it particularly likely that older adults’ initial retrieval of positive content impairs their ability to later remember related, negative content (Aim 3) and leads to broader age- related differences in the details accessed over successive retrievals such that, over repeated retrievals, older age is associated with memories that become more positive (Aim 4).

NIH Research Projects · FY 2025 · 2022-08

Brain Healthy builds upon the success of BrainWaves, a prior NIH Science Education Partnership Award (SEPA)-supported program, which has been successfully implemented in 25 public New York City schools, reaching over 600 students. Our new proposed program, Brain Healthy, is responsive to one of the new areas of high SEPA programmatic interest: providing students with access to research-generated data to prepare students for data science careers. Brain Healthy will be designed by a multidisciplinary team across Boston College, the University of Connecticut and New York University in partnership with teachers in Massachusetts, Connecticut, and New York. Students in the program will first participate in a large-scale “citizen science” research project by taking a comprehensive survey (partially developed by students themselves) about their health and lifestyle practices. Students will also measure their heart rate with fitness trackers and complete a computerized cognitive (Stroop) task and mood survey. They will learn about brain plasticity and how positive (e.g., physical exercise) and negative (e.g., stress) life experiences impact our brain. With support from near-peer mentors (NPMs), students will then design data-driven investigations utilizing the entire de-identified citizen science database collected across all the participating schools, exploring questions, such as how sleep quality relates to mood and how fitness level associates with ability to focus. The Brain Healthy platform will guide students through these investigations by providing scaffolding in critical steps of the process. The program will culminate in a school-wide science fair, where students will share their findings with the wider school community. The program will be accompanied by professional development (PD) courses for teachers and NPMs prior to school implementation with additional just-in-time support. The main educational research questions are how does participation in a “citizen science” brain health and wellness program impact: 1) Students’ conceptual understanding of data analysis and brain plasticity, and their attitudes toward STEM; 2) Teachers’ self-efficacy in facilitating data-driven student investigations; 3) NPMs’ mentoring ability and intent to persist in STEM. Three cohorts of 10 teachers will be recruited, each participating for three years, with the first year occurring prior to the Brain Healthy PD course (serving as a well-matched comparison). Across the 5- year project, ~1500 students are expected to participate in Brain Healthy. Project evaluation will utilize pre- and post-program surveys, semi-structured interviews, and classroom observations.