Dartmouth College

NIH Research Projects · FY 2026 · 2025-01

During embryogenesis, the formation of body plan is largely driven by remodeling of epithelial tissues. While epithelial morphogenesis is regulated biochemically by genes and molecules, it is also an intrinsically mechanical process controlled by cellular forces and tissue mechanical properties. Despite significant progress in deciphering the genetic and biochemical determinants of force generation, little is known about how tissue mechanical properties are regulated and how this regulation impact morphogenesis. The proposed study addresses these questions in the context of epithelial folding, a fundamental tissue construction mechanism in development. Using Drosophila gastrulation as a model, our recent studies have elucidated how local tissue mechanical properties and global mechanical coordination are exploited by the embryo to facilitate mesoderm invagination, and how these apparent “passive” tissue properties are regulated by active cellular processes and feedback mechanisms. During gastrulation, mesoderm precursor cells constrict their cell apex and subsequently invaginate from the surface of the embryo by forming a ventral furrow. We found that as the tissue constricts apically, the tissue interior behaves as a viscous continuum and forms a laminar flow. This viscous response involves prompt cell surface expansion that relies on the function of the PI 4-kinase Four Wheel Drive (Fwd). In addition, we found that the transition from apical constriction to mesoderm invagination relies on compressive forces generated in the surrounding ectodermal tissues, which facilitate tissue folding by promoting mechanical bistability in the mesoderm. This long-range mechanical coordination is contingent on effective mechanical coupling between the mesoderm and the ectoderm. Finally, we found that the embryo employs a feedback mechanism involving Rab11-mediated vesicle trafficking to reinforce the physical integrity of the supracellular actomyosin network, allowing the tissue to promptly adapt to a rapid increase in tissue tension. In the proposed study, we will use a multipronged approach combining genetics, optogenetics, quantitative live-imaging, cell biology and biophysics to (1) investigate the mechanism underlying Rab11-medaited feedback regulation of actomyosin during apical constriction, (2) determine how PI-4 kinases and their product, PI4P, regulate force-induced cell surface expansion and how cell surface “expandability” determines local and global tissue mechanical properties, and (3) determine how tissue compression is generated in the ectoderm to promote long-range mechanical coordination during mesoderm invagination. Successful completion of our research goals will advance scientific knowledge by elucidating the regulatory networks and physical principles that dictate how tissues generate, sense and respond to mechanical forces to establish proper form and function in development.

NIH Research Projects · FY 2026 · 2025-01

ABSTRACT Chimeric antigen receptor (CAR) T cells are remarkably effective against advanced hematologic tumors, mediating complete remission in >50% of patients. Yet they have limited success against solid tumors due to the immunosuppressive tumor microenvironment (TME). To improve efficacy, CAR T cells can be “armored” with growth factors, such as IL-2 and IL-15, to promote expansion and survival within the TME. Alternatively, “arming” CAR T cells with inflammatory cytokines amplifies antitumor responses by activating host T cells. We recently armored and armed CAR T cells with an IL-2 superkine (Super2) and tissue alarmin IL-33 (hereafter, Super2+33). These cytokines act synergistically and, with multiple CAR constructs, to alter the TME to promote regression of primary and metastatic solid tumors. However, the ability of CAR T cells to provide durable antitumor immunity remains an open question. Analysis of two long-term survivors who received CD19-targeting CAR T cells shows decade-long persistence of CAR T cells, leukemia regression, and loss of normal B cells. Clinical responses are also positively associated with transcriptional features of stem cell memory T (TSCM) cells in the manufactured CAR T-cell product. These data have spurred the field to optimize in-vitro manufacturing conditions to increase memory T-cell potential within the CAR T-cell product. However, the in-vivo fate of individual CAR T cells within a heterogenous CAR T cell population, such as each cell's ability to proliferate, infiltrate tumors, kill, and differentiate into memory T cells, remains unknown. Moreover, it is unclear how CAR engineering and host environmental factors impact the heterogeneity of CAR T cell effector and memory responses. We will test the overall hypothesis that CAR T-cell heterogeneity can be deconvolved to understand how individual T cell subsets behave in vivo and that principles gained through these analyses can help us rationally engineer CAR T-cell populations that balance antitumor effector responses with generation of durably protective antitumor CAR and host circulating (TCIRC) and widely distributed tissue resident (TRM) memory T cells. This hypothesis will be tested in three aims. Aim 1 will use using dynamic lineage recording to deconvolve CAR T cell heterogeneity to reveal individual differentiation trajectories and identify engineering strategies to program CAR stem cell-like (TSCM) and TRM cell fates. Aim 2 will determine the respective requirements for host and CAR T-cell memory. Aim 3 will identify the effect of tumor burden and neoadjuvant immune checkpoint blockade on T-cell precursor subsets and states on CAR T cell differentiation. Successful completion of this study will advance the development of durable adoptive CAR T-cell therapy for melanoma that results in globally distributed memory T cells with optimal fitness and function.

NSF Awards · FY 2025 · 2025-01

The broader impact of this Partnerships for Innovation – Technology Translation (PFI-TT) project is in addressing the needs of current and next-generation human-electronic tactile feedback systems. Tactile feedback systems, also known as haptic systems, provide physical sensations to users to simulate the feeling of touch. The haptic systems have been severely constrained by the need for small size, low cost, and effective electronics. Such systems can provide new dimensions of human control, feedback, and interaction, benefitting a range of consumer, medical, military, industrial and automotive applications, but require very high voltage drive electronics that have historically limited adoption and commercial viability. This research addresses the power electronics platform, reducing size and cost while improving efficiency and exploring application-specific feature sets. Activities include the design and fabrication of a custom integrated circuit and assembled platform, further exploration of pre-commercialization needs through dialog with industry and commercialization expert(s), training of students in technical, leadership, and entrepreneurial areas, as well as broader dissemination of technical and research findings through publication and outreach. This project explores new power electronics architectures that use high energy density switched capacitor-based switching amplifiers to provide high driving voltages while efficiently providing and recovering reactive drive energy. This project includes the design of a novel hybrid-switched-capacitor circuit, reducing quantized hard-switching loss, improving digital-analog waveform synthesis, and reducing auditory and electromagnetic interference. The hybrid architecture helps reduce passive component size and volume by an order of magnitude compared to conventional boost converters by using a stacked/hierarchical design in Silicon-On-Insulator (SOI) Complementary Metal-Oxide-Semiconductor (CMOS). The design will use low-voltage semiconductor devices (which are smaller and more efficient) to generate up to 400 Volts from a low-voltage CMOS-compatible supply or battery, while using networked communication for closed loop control. The switched-capacitor approach enables order-of-magnitude size reduction compared to conventional boost converters, thus is more scalable to high voltages, easier to integrate, and can efficiently recycle energy stored in the actuator, helping address technical bottlenecks and support a path to commercialization. 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 · 2024-12

ABSTRACT Antibody effector functions represent a nexus linking innate and adaptive arms of the immune system and also have direct clinical implications for antibody therapeutics and antibody-mediated pathologies. However, the potency of Ab-dependent effector responses depends on numerous antigen, antibody and effector cell properties. Variable antigen expression levels, accessibility and context on different targets influence not only Ab binding but also the ability of the effector cell to kill or engulf its target. Based on the extensive diversity of natural and engineered antibody forms and formats, both B cells and immunologists can engineer antibodies with different flexibility, affinity, and avidity to manipulate the effector response. The complexity of these interactions makes in vivo experimental testing of all combinations impractical, but the significance of these activities to antibody-based protection and pathology and the opportunity to design agents with a high probability of success once the fundamental cellular presentation mechanisms are understood makes quantitative analysis of this complex biological landscape of high significance. This proposal will elucidate our basic understanding of the cellular mechanisms that can drive advancements in the practical development of immune therapeutics and the parameters by which both B cells and effectors can drive variation in the outcome of antibody recognition. Overall, this work seeks to distill quantitative relationships between antigen, antibody, and effector biology to establish “rules” that enable the generation of antibody design criteria that encapsulate key landmarks in the antibody effector function landscape and enable robust prediction of this critical aspect of antibody activity.

NSF Awards · FY 2024 · 2024-12

NON-TECHNICAL SUMMARY The room-temperature solubility of small atoms such as carbon and boron in some traditional metals such as nickel and aluminum are very low and, thus, their solute strengthening effect in these metals is also very low. Recently, it has been shown that elements such as carbon and boron can have large solubilities in exciting new classes of alloys called high-entropy alloys and medium entropy alloys, and thus can significantly increase their strength. Such alloys are potentially useful in demanding engineering applications. This project will quantify the phenomenology of this strengthening effect and using advanced microstructural characterization techniques determine the underlying mechanisms of the strengthening. The project will be undertaken by the Principal Investigator, a Ph.D. student, and several undergraduates. For professional development, the graduate student will take both a teaching training course and ethics training. The public will be engaged both through outreach to local high schools for which some simple, inexpensive experiments will be developed that demonstrate some Materials Science phenomena, and at Science Pubs, in which community members and researchers have lively conversations about science topics. Research results will be published in refereed journals, presented at conferences, and archived in on-line databases. TECHNICAL SUMMARY The aim of the project is to understand both the phenomenology and micromechanisms of interstitial strengthening in f.c.c. high entropy alloys (HEA) and medium entropy alloys (MEAs). The working hypothesis is that interstitials have substantial effects on dislocation behavior (and, hence, mechanical properties) by changing slip from wavy to planar due to an increase in the friction stress (possibly due to short-range order, SRO), or a change in the stacking fault energy (SFE). To that end, the project will: determine the effects of interstitials on the stress-strain curves of single-slip-oriented single crystals, followed by post-mortem examination, using a TEM and an SEM, of the defect structure of crystals strained to various elongations; perform in situ deformation experiments in a TEM and an SEM, and use neutron diffraction to determine the dislocation behavior in detail; determine, using X-ray diffraction (XRD), STEM (including electron diffraction and X-ray spectroscopy), and atom probe tomography (APT), the effects of interstitials on the lattice (the size mismatch parameter, the modulus mismatch parameter, SFE, SRO) and their segregation to dislocations both before and after straining; and determine the exponents in the relationships between the increase in yield strength and both the interstitial concentration and the mismatch parameters. The work will be performed on the HEA/MEAs Fe40Mn40Co10Cr10 and CoCr0.25FeMnNi doped with various interstitials, and, time permitting, Fe40.4Ni11.3Mn34.8Al7.5Cr6. The work will involve synchrotron XRD measurements at the Argonne National Laboratory, and both in situ straining neutron diffraction studies and APT studies at the Oak Ridge National Laboratory. 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 · 2024-12

Abstract It has been highly challenging to scale up non-genetic, sub-second neuromodulator sensing or integrate it with electrical recording. Recently, we discovered that mild annealing dramatically improved the electrochemical stability of electroplated carbon coating and transformed conventional microelectrodes into sensors similar to carbon fiber electrodes with excellent neuromodulator-sensing performance based on fast-scan cyclic voltammetry (FSCV). Compared to previous carbonization strategies such as pyrolysis of polymer and laser- induced graphitization, low-temperature, FSCV-stable carbon coating is directly applicable to microelectrode arrays (MEAs), enabling unprecedented spatial scaling of FSCV and unparalleled integration with electrophysiological (ephys) recording, while leveraging decades of MEA research and applications. As a demonstration, we have created a monolithic MEA probe with integrated ephys and FSCV capabilities and validated it in vivo in multiple rodent models. Early studies using this probe in awake rats further revealed an unprecedented correlation between striatal gamma oscillation and dopamine release. In three parallel aims, we intend to optimize, benchmark, and thoroughly validate the platform ephys-FSCV MEA probe for high-density neuromodulator sensing and parallel electrical recording in behaving animals. Our multidisciplinary team consists of a materials scientist and neural engineer (Fang) and a systems neuroscientist (van der Meer), who have jointly produced strong preliminary results with successful in vivo validation and neuroscience studies. In addition to establishing the significant and novel multimodal MEA paradigm, which we envision will enable numerous studies in basic and translational neuroscience, we anticipate that the concept of FSCV-stable carbon-coating and the bioengineering of its up-scaling and ephys-integration are generalizable to many other probes, such as DBS and sEEG electrodes and extensible to further technology evolutions and commercial manufacturing.

NIH Research Projects · FY 2026 · 2024-12

Project Summary The neuronal endoplasmic reticulum (ER) extends throughout the cytoplasm and forms extensive physical contacts with organelles, even within specialized compartments like the presynaptic terminal. These contact sites between the ER and other organelles are termed membrane contact sites (MCSs). MCSs are held together by tethering proteins and are proposed to contribute to at least three cellular functions: trafficking of lipids, organelle positioning, and exchange of calcium (Ca2+) ions. During action potential (AP) signaling, the influx of Ca2+ through voltage-gated Ca2+ channels forms localized Ca2+ microdomains. These Ca2+ microdomains are critical for synaptic vesicle fusion, signaling through Ca2+-sensitive proteins, and organelle function. MCSs are thought to contribute to Ca2+ exchange by recruiting ER-bound proteins and organelles to Ca2+ microdomains, although it is unclear which organelles are most reliant on tethering to the ER. A fundamental gap exists in understanding the molecular composition and function of tethering proteins in the axon. The development of optogenetic Ca2+ indicators of different affinities has provided unprecedented opportunities to study how MCSs in the axon link electrical activity with Ca2+ signaling to support synaptic function. VAMP-Associated Protein (VAP) is a highly conserved ER tethering protein that binds numerous intracellular targets. In the axon, VAP forms a unique MCSs by binding to voltage-gated potassium (Kv) channels Kv2 at the plasma membrane (PM). Disrupting these ER/PM MCSs by knocking down Kv2 channels impairs synaptic vesicle exocytosis by ~50% and requires VAP interactions in the Kv2 C-terminus. Unexpectedly when VAP is knocked down in excitatory neurons, there is no change in AP-evoked cytosolic Ca2+ despite a ~50% impairment in exocytosis. The central hypothesis is that Kv2/VAP MCSs are an essential structural component of presynaptic terminals for Ca2+ signaling microdomains to support synaptic function. The overall objective is to determine at what level membrane tethering affects synaptic function. The long-term goals are to determine how membrane tethering informs synaptic strength and how dysregulation of these processes are involved in disease. Aim 1 will determine how VAP domains contribute to synaptic function using optical indicators of synaptic vesicle exocytosis. Aim 2 will determine how VAP MCSs influence Ca2+ dynamics within axonal organelles using subcellular optical indicators of Ca2+. Given the complexity of this system and the essential nature of electrical signaling in excitable cells, it is unsurprising that mutations in VAPB are implicated in several diseases including familial amyotrophic lateral sclerosis. There is a critical need for a better understanding of the role of membrane tethering in intracellular Ca2+ dynamics in the axon that we know is critical for synaptic function.

NIH Research Projects · FY 2026 · 2024-12

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is one of the primary reasons for memory dysfunction and dementia after 60 years of age. Neuronal dysfunction and death in the frontal cortex and hippocampus, along with microglia-mediated neuroinflammation and formation of aberrant protein aggregates and fibrils are hallmarks of AD. Sporadic and familial forms of AD have an overproduction and/or decreased clearance of extracellular amyloid-beta (Aβ) peptides and intraneuronal tangles of twisted tau protein fibers. Neuroinflammation is known to occur in AD, and when associated near Aβ plaques there is a greater neurodegeneration. Data suggest that inflammatory microglia, the resident macrophages of the central nervous system, have a role in neurodegeneration and cognitive decline. Aberrant innate immune responses and altered inflammation are associated with AD and are involved in AD disease in murine models. Data show that inflammation modulators may be beneficial, but a challenge is how to delivery anti-inflammatory therapy that provides multiple mechanisms rather to the site of disease. T regulatory cells (Tregs) are a subset of T cells that have inherent anti-inflammatory activity. Tregs are found in the CNS under steady state conditions and increase in regions of CNS inflammation. Although the overall role for Tregs in AD is not well understood, many studies support a potential beneficial role for Tregs in AD. Our therapeutic strategy is to target Tregs to rebalance cerebral immunity, promote Aβ clearance, and limit neuron damage. However, key challenges for Treg therapy are that polyclonal Tregs do not target disease-associated antigens and there is no IL-2 in the CNS to support Treg persistence. We hypothesize that chimeric antigen receptor (CAR) Tregs targeted to AD-associated antigens that are engineered to persist will solve these key problems. We have chosen to use CARs that bind aggregated amyloid-beta (A-β), so that the CAR Tregs will be triggered at the site of A-β plaques. CAR cell therapy is a great approach for therapy because cells as drugs can traffic to sites of disease, persist in vivo (when engineered to do so), respond to the environmental cues (e.g. antigen) to trigger or limit activities, and delivery multiple therapeutic mechanisms.

NSF Awards · FY 2024 · 2024-11

Geometry and arithmetic were first studied by the Greeks, while algebra first emerged centuries later in the hands of Persian scholars as the art of solving equations. The interplay between these three disciplines has been at the center of mathematical research over the past century. Mathematicians have uncovered deep connections between them, leading to many spectacular results in mathematics (e.g., Fermat’s Last Theorem) and other fields, including applications in cryptography, quantum field theory, and string theory in physics. The main object of study at the intersection of these disciplines is a set of algebraic equations. While geometry helps understand the shape of the set of solutions with complex entries (also called algebraic varieties), the goal of arithmetic is to understand the set of solutions with integer entries. There are natural linear structures attached to algebraic varieties called Hodge structures, which in some cases capture faithfully the set of algebraic equations we started with. The study of Hodge structures, their symmetries, and their variations is the main object of investigation of this proposal. It is a topic at the crossroads of several areas of research such as complex algebraic geometry, number theory, and representation theory, with many long-standing conjectures. The PI will involve graduate students in this project and will organize a conference on recent advances in Hodge theory. This project aims to answer several questions regarding the distribution of the exceptional Hodge locus in the theory of variations of Hodge structures and their arithmetic counterpart, the Tate locus. These questions will be addressed using tools from Arakelov intersection theory, ergodic theory, Hodge theory, Ax-Schanuel theorem for Shimura varieties, and Diophantine geometry. The first goal is to study the atypical Hodge locus in some families of algebraic varieties. The second goal is to study the Tate locus and give a concrete application to exceptional algebraicity under specializations of Brauer classes on K3 surfaces. The third goal is to study the modularity behavior of the closure of special cycles in moduli spaces of K3 surfaces, or more generally in orthogonal Shimura varieties. These generating series exhibit a quasi-modularity behavior as well as a mixed mock modularity behavior, depending on the type of degeneration of the family of K3 surfaces. 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 · 2024-11

Project Summary Human cytomegalovirus (HCMV) is a ubiquitous and medically significant pathogen which causes severe morbidity and mortality among immunocompromised populations. HCMV, a betaherpesvirus, enters lifelong quiescent persistence in the infected host known as latency. Latency is very complex but is known to require the participation of both host and viral factors, and inhibition of either can lead to a loss of latency in ex vivo model systems. HCMV specifically co-opts innate cellular antiviral signaling via the interferon alpha receptor (IFNAR) signaling pathway, which leads to the activation of signal transducer and activator of transcription 1 (STAT1). STAT1 acts as a transcription factor, binding to a conserved DNA motif known as an interferon- stimulated response element (ISRE) and initiating transcription of interferon stimulated genes (ISGs) which are essential for antiviral defense. During normal cellular homeostasis, activated STAT1 (pSTAT1) is rapidly dephosphorylated resulting in cessation of signaling, however, HCMV maintains STAT1 phosphorylation at high levels through 72 hours. Maintenance of pSTAT1 during infection requires the viral protein UL138 in complex with host UAF1 and USP1, and inhibition of these proteins prevents the establishment of latency, suggesting that pSTAT1 signaling is essential for viral persistence. HCMV also appropriates pSTAT1 by recruiting it to the viral genome, where it binds to viral ISRE sequences, suggesting the existence of viral ISGs. In this proposal we seek to determine the mechanisms by which HCMV maintains STAT1 phosphorylation during infection and the impacts of this prolonged signaling on viral replication and latency. We hypothesize that HCMV manipulates the IFNAR1 signaling pathway to phosphorylate STAT1, thereby inducing transcription of viral genes and promoting viral latency. Our goal is to answer two overarching questions. First, how does HCMV maintain STAT1 signaling? We hypothesize that HCMV licenses STAT1 interaction with IFNAR by removing inhibitory ubiquitin moieties, while simultaneously impeding sorting endosome turnover to prolong IFNAR complex stability and signaling. Second, what is the impact of UL138-induced STAT1 signaling? We hypothesize that STAT1 signaling is used by HCMV to regulate transcription of its own genes and to alter the intracellular environment to promote latency. Answering these questions will provide new insight into viral and cellular processes involved in the pathogenesis of this important human pathogen and potentially lead to novel approaches to therapeutic or curative treatments.

NSF Awards · FY 2024 · 2024-10

Prostate cancer is the second most common cancer diagnosis, which can potentially be cured by surgically removing the prostate. Unfortunately, in one out of five cases, removing the prostate still leaves behind some cancerous cells, requiring additional treatment that often has serious side effects. This project will develop an innovative, intelligent surgical probe that allows the surgeon to check that all cancerous cells are removed during the prostate removal surgery. Creating this surgical probe will require fundamental research on how to sense and analyze the properties of the prostate tissue with sufficiently low power and small size to fit into the probe. The same underlying technology will be useful beyond prostate cancer treatment, including in (1) preventing injury to nearby nerves during tooth implant surgery; (2) continuously monitoring the brain after it has experienced physical injury; and (3) measuring blood pressure from a smartwatch. The novel technology that this project will build is an edge artificial intelligence (AI) system-on-chip for bioimpedance analysis that will check the periphery of the tissue being removed, known as surgical margins, for cancerous cells during the surgery. This chip is based on two concepts for applying analog signal processing to bioimpedance analysis: (1) an adaptive filter that removes the baseline from bioimpedance signals; (2) a new type of gated recurrent neural network that is implementable as a small, analog circuit but performs with similar accuracy as a large, discrete-time system. To evaluate the chip, it will be integrated into a surgical margin assessment probe and tested on how accurately it can distinguish cancerous from healthy tissue in resected prostates (retrieved from men that have undergone prostatectomy as part of their standard of care). The project will make contributions to edge AI by developing a new analog gated recurrent neural network paradigm that is several times more power- and area-efficient than the state-of-the-art. The project will also make contributions to the field of bioimpedance instrumentation by enabling high frequency bioimpedance analysis in a millimeter-scale form factor, thus providing new capabilities in surgical, implantable, and lab-on-a-chip applications. This project is jointly funded by the Smart Health program (SCH) and the Established Program to Stimulate Competitive Research (EPSCoR). 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 · 2024-10

This project transforms engineering education by leveraging "meaningful failure" as a promising approach to learning and teaching. Failure is an inherent part of human life and learning processes, and early failure is often prerequisite step on the path to successful learning. However, typical engineering education currently punishes failure, which disincentivizes innovation, exploration, and risk-taking, ultimately resulting in engineers who are less prepared to tackle complex global challenges. By understanding students’ unique experiences during moments of academic failure, this project supports students taking risks and learning from setbacks, developing the skills and mindsets to embrace failure as a meaningful experience in their learning. Our research involves the use of biometric data, observations of classroom dynamics, and psychosocial assessments to better understand how each student experiences failure on a physiological, cognitive, and social level. We will use these data to develop new educational tools and strategies that will provide immediate, tailored interventions connected to individual student needs and experiences. This research will support the development of a workforce ready to persist past ubiquitous failure experiences in engineering to address tomorrow’s challenging engineering problems. Further, this research aligns with the goal of creating inclusive and equitable learning environments that can adapt to the diverse needs of all students. The project will explore meaningful failure in engineering education contexts by developing personalized learning strategies and pedagogical tools. The proposed research has three goals: identifying real-time failure profile signals, understanding how learners' responses to failure are individualized, and determining necessary changes in pedagogy and assessment to support personalized responses tolearning from failure. The research involves a multi-pronged data collection approach, including laboratory experiments using video and biosensing modalities (EEG, EDA, ECG), classroom observations, surveys, and interviews with educators and administrators. A convergent team from five institutions, with expertise in cognitive neuroscience, learning sciences, AI, and psychosocial theories of learning and development collaborate to create individualized failure profiles. These profiles will integrate multi-modal data sources to formally represent each learner’s unique cognitive, affective, and behavioral responses to failure. The project will culminate in the development of pedagogical tools and strategies to support personalized learning and resilience – increasing retention and success rates in engineering fields and pioneering a shift in engineering education towards valuing learning from failure. 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 · 2024-10

In addition to experiential learning, where people learn from the outcomes of their own choices, people also acquire a substantial amount of knowledge by observing friends, relatives, and others within their social network, a phenomenon referred to as social learning. Not surprisingly, social networks play a crucial role in transmission of information across society. This project examines the relationship between social and experiential learning to shed light on mechanisms by which the brain learns from interactions with others in a social network. In addition to the research, the project also includes interdisciplinary experiences for trainees and outreach to K-12 students. A deeper understanding of the neurocomputational mechanisms of social learning within social networks requires identifying both fundamental computational principles and the brain systems that perform these computations. This project aims to establish a basis for such understanding by leveraging computational modeling and model-based neuroimaging experiments to explore the similarities and differences between one-shot averaging typically assumed in social learning and error-driven reinforcement learning. Specifically, the project examines how the uncertainty and volatility of the environment, along with the topology of the social network, influence the preference for one-shot averaging versus error-driven updating. It also aims to identify brain areas involved in these learning processes and their arbitration. By doing so, it provides a unique link between the fields of cognitive, behavioral, and social neuroscience that could fundamentally advance our understanding of social cognition. A companion project is being funded by the French National Research Agency (ANR). 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 · 2024-10

The human head houses many important physiological signals such as brain signals (EEG), facial muscle signals (EMG), eye signals (EOG), etc. which have tremendous value in inferring the user's mental, physiological, and physical states. In addition, it also serves as an ideal body part for applying brain stimulations. However, most of the existing head-based sensing and stimulation methods are cumbersome, intrusive, and expensive, mostly suitable only for stationary and short-term usages such as in clinics or hospitals. This project aims to fill that gap by enabling a novel form of wearable sensing and actuating systems that can unobtrusively, continuously, comfortably, and simultaneously sense a multitude of head-based physiological signals and actuate to stimulate the brain while remaining minimally visible to the public. While the well-accepted form factors for wearable devices are watches, glasses, and other kinds of body-worn form factors, this work takes a drastically different approach, an ear-worn sensing and actuation approach (called Earable Systems) to tame a problem that has long hindered the deployment of head-based wearable systems, namely user acceptance, by making the wearable devices more socially acceptable and less visible to the public. The intellectual merit of this project stems from the key research activities. The activities include: formulating multiple head-based signal propagation models to and from human ears using superposition principle of wave propagation; developing algorithms, experimental hardware blocks, analytical models, and software libraries for sensing individual head-based physiological signals; developing closed-loop stimulation techniques, associated hardware, analytical tools, and safety guidelines for effective and safe just-in-time brain stimulation from the ears; and evaluating Earable Systems and the proposed platform in-lab for a compelling and practical application. This project's broader impacts stem from an integrated program of education, research and outreach that will translate the research results into demonstrations and hands-on experiences for under-served middle school students and local teachers through lab visits and summer workshops. It will also provide a unique interdisciplinary education for future engineering and healthcare workforce. It will also provide insight to future healthcare technologies through two Open Online Courses (MOOCs) for clinicians and undergraduate engineering students. And, both undergraduate and graduate students will be involved in advanced interdisciplinary healthcare projects using Earable Systems concepts. The research has the potential to translate scientific discovery and technical knowledge into beneficial commercial products through industry outreach and internships. 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 · 2024-09

Opioid misuse is a public health crisis in the United States, affecting almost 700,000 women of reproductive age in 2022. Opioid use disorder (OUD) has intergenerational impacts; infants born with prenatal opioid exposure have increased risks of neonatal opioid withdrawal syndrome (NOWS), preterm delivery, congenital abnormalities, and poor intrauterine growth. However, at a population level, our knowledge of the health and developmental trajectories of opioid-exposed children following discharge from their birth hospitalization is extraordinarily scant. The overall goals of this project are to characterize health outcomes during the critical period of birth to five years of age in children born to people with OUD and ascertain protective health system factors using data from the Texas Neonatal Care Research Collaborative, which uniquely links Medicaid healthcare claims, birth certificate data, mortality files, and data from the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) program. Given past research showing that a NOWS diagnosis may be protective against infant mortality in opioid-exposed infants, this work will first examine variation in the diagnosis of NOWS across 150 hospitals, characterize variation in NOWS diagnosis rates, and determine the extent to which variation in NOWS diagnosis rates may be explained by clinical, social, and birth hospital factors. Second, this work will determine the cumulative incidence of neurodevelopmental and complex chronic medical conditions at five years of age in children with prenatal opioid exposure relative to children without this exposure, examining how these outcomes differ between children with and without a history of NOWS. Third, this work will identify health system factors that are protective against infant mortality and neurodevelopmental and complex chronic medical conditions at 5 years of age. A research team comprised of multidisciplinary clinicians, statisticians, data scientists, and key policy and program stakeholders will conduct a population-level analysis of 1.7 million maternal-infant dyads insured by Medicaid using data from 2010-2023. Investigators will develop multi-level models to account for the hierarchical data structures, adjusting for confounding variables and identifying health system factors associated with positive child health outcomes. Completion of this work will rapidly address a key knowledge gap regarding the developmental and health trajectories of children born to people with OUD, characterizing modifiable health system factors that may be leveraged to improve both maternal healthcare and child health.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY: The opioid crisis has devastating impacts, resulting in $35 billion in healthcare costs, $92 billion in lost productivity, and over 100,000 deaths annually. Effective treatment with Medications for Opioid Use Disorder (MOUD) like methadone or buprenorphine can significantly reduce opioid-related mortality. However, individuals with Opioid Use Disorder (OUD) face critical unmet information needs about MOUD treatment, often turning to social media due to stigma, lack of trust, and resources. This project aims to leverage Natural Language Processing (NLP) and mixed methodologies to identify and classify medication treatment information needs of individuals with OUD on Reddit, a popular social media platform. The goal is to extract clinically relevant insights to improve MOUD treatment access and quality. Three specific aims guide this project: AIM 1: Identify buprenorphine- and methadone-related TINs self-reported by persons with expressed opioid use disorder on Reddit. A large dataset of relevant Reddit posts will be curated, and a qualitative coding protocol developed to systematically identify MOUD treatment information needs. AIM 2: Evaluate feasibility of reliably classifying buprenorphine and methadone-related TINS on Reddit using state-of-the-art NLP methods to enable efficient extraction of MOUD TINs on social media. Success will be defined by achieving an F1 score of 80% or higher and statistically significant improvements over standard baseline models. AIM 3: Characterize the nature of peer engagement on Reddit to identify areas of MOUD misinformation and information gaps, promoted self-treatment strategies, and stigma. Both quantitative and qualitative methods will be employed to achieve this aim. The impact of this project is significant, as it will produce new, validated methods for efficiently extracting actionable insights from social media data. The outcomes align with priorities outlined by the National Institute on Drug Abuse (NIDA), including leveraging data science to understand real-world complexity and developing personalized interventions informed by people with lived experience. This work will establish a foundation for future proposals aimed at advancing computational health in the context of substance use disorders.

NIH Research Projects · FY 2026 · 2024-09

One-in-five children and adolescents in the United States (US) live in rural areas where they experience approximately two times the risk of suicide compared with their urban-residing peers. Despite having increased rates of mental and behavioral health conditions, less than half of rural residing youth with these conditions receive necessary treatment, due in part to shortages of pediatric services and clinicians. Given barriers to community-based mental healthcare, youth with suicidal ideation and/or attempt increasingly present to emergency departments (EDs) for care. While several national organizations endorse safety planning (a brief intervention that involves identification of coping strategies, social supports, and lethal means restriction) in EDs as an evidence-based suicide prevention intervention, implementation in rural settings requires consideration of the unique rural context as well as hospital and community resources. The overall goal of this project is to develop and implement a technology-aided approach to safety planning that will specifically address two dimensions of health – home safety and access to community mental healthcare – to decrease suicide risk in youth 12-17 years of age who present to rural EDs. To achieve this goal, investigators will: (i) conduct focus groups and interviews with rural-residing youth, their caregivers, clinicians, and community members to ascertain their priorities and perspectives about how to optimize safety planning, including lethal means counseling and community resource connections, in rural EDs; (ii) apply principles of human centered co-design to develop and test a youth- and caregiver-facing tablet-based digital intervention to guide safety planning, using mixed methods to investigate its feasibility, acceptability, and appropriateness, and to evaluate participant-reported self-efficacy to improve suicide-related coping and home safety (target mechanisms); and (iii) conduct a type 1 hybrid implementation-effectiveness study using a hospital-randomized stepped wedge design in four rural EDs to determine the effectiveness of this intervention compared to usual care for youth with suicidality, evaluating the extent to which outcomes are mediated by caregiver and youth selfefficacy, and assessing the reach, adoption, implementation and maintenance of the intervention using a mixed methods approach. Primary outcomes, measured one and three months following the ED visit, will include youth-reported suicide risk, evaluated using a validated instrument, and caregiver-reported home safety.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Determining whether a tumor has spread to the regional lymph nodes is critical for staging and treatment planning for several types of cancer, including cancers of the head and neck. This determination is routinely performed surgical removal of regional nodes for cancers of the head & neck. While widely accepted and proven to be effective for tumor staging and limiting the further spread of the disease, surgical removal of lymph nodes can lead to morbidity and small metastatic deposits may remain undetected due to pathological sampling error. Thus, patients who undergo the procedure may receive a suboptimal treatment plan. In this project, we will develop a noninvasive ultrasound-based molecular imaging tool to identify micrometastases in the lymphatics. We will develop perfluorocarbon nanodroplet contrast agents targeted to cell surface receptors via directional conjugation of antibodies. We will synthesize two classes of nanodroplets, each with a different boiling point and molecular target. One nanodroplet formulation will be targeted to the epidermal growth factor receptor (EGFR) to enable molecular detection of cancer cells, while the other will be untargeted to act as a delivery control. Based on the phase-change behavior visualized in ultrasound images, we will differentiate between the EGFR- targeted nanodroplets and the nonspecific control. Then, we will apply ratiometric and kinetic modeling strategies to use the different accumulation patterns to highlight regions with small metastases. The nanodroplets and imaging methods will be tested in polyacrylamide phantoms before the dual tracer design is applied to a small animal model of head and neck cancer metastasis. The overall result will be a method that can detect small pockets of metastases in the lymphatics several centimeters deep in tissue.

NSF Awards · FY 2024 · 2024-09

Many languages are endangered, including numerous Indigenous languages. Because endangered languages have strong linguistic and cultural significance, as well as scientific value as a component of linguistic infrastructure, it is important to support and inform documentation and revitalization efforts for these languages. Modern technologies, including infrastructure to archive large-scale collections of recordings and computer-based analysis tools, have strong potential to facilitate documentation efforts. However, not all stakeholders have access to these technologies. This project advances knowledge concerning the necessary training and resources required to support effective and inclusive use of technology in the context of endangered Indigenous languages. This work is timely because many language communities are faced with urgent needs to develop language technology to support documentation efforts. This project provides education for students and community members. It also benefits society by expanding language technology development to include Indigenous language community members, a significantly underserved population. Sustainable language technology development must be consistent with the needs, practices, and values of the communities undertaking the work, and, in many cases, is best done within the communities themselves. This community-based project addresses problems that stem from difficulties in access to technology infrastructure in Indigenous communities and linguistic biases built into existing computational technologies. In doing so, it incorporates communities' needs, practices, and values regarding data sovereignty and appropriate access to language materials. Using a multidisciplinary and multi-institutional approach, the project builds capacity and infrastructure to support the development of effective, durable, and appropriate language related technologies by Indigenous communities. The project creates a network of diverse individuals who share expertise, resources, and tools for capacity development in addition to resources needed to create and maintain language-related technologies (e.g., applications, websites, keyboard inputs, dictionaries) and natural language processing and AI technologies (e.g., speech-to-text, text-to-speech, predictive text, machine translation). This project yields a sustainable set of technological supports that integrate with community values and advance ongoing Indigenous language revitalization. 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 · 2024-09

Heart disease is difficult to study. Animal models are not always effective; neither are most cell culture studies. This leads to many failed drug developments. Scientists are now using human stem cells to make more faithful human cardiac models for research. One problem is that these cells are still immature, making it uncertain how well they can model disease. To develop a more effective representation of a heart, an attempt will be made to create a “heart on a chip”. The current standard methods of cardiovascular research are based on static two-dimensional cell cultures and animal models. They both have significant limitations. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have shown to be promising as an alternative for these in vitro studies. However, a key bottleneck in the current applications of hiPSC-CMs lies in their structural and functional immaturity, leading to less predictive results in disease modeling and drug toxicity tests. By employing biochip design, machine learning, developmental biology, and tissue engineering, this project will build the foundation for overcoming this obstacle and develop methodologies for an efficient and rational manufacturing pipeline of mature hiPSC-CMs. To achieve this goal, the team will develop models to understand cardiac cell-cell and cell-matrix interaction dynamics needed in enhancing the maturity of hiPSC-CMs using microchip engineering with artificial intelligence-driven feedback. The ability to manufacture mature hiPSC-CMs at scale and speed could accelerate drug and cardiac disease model development. 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 · 2024-09

River floods in hilly and mountainous areas have caused billions of dollars in damage to homes, businesses, roads and bridges over recent decades. Local communities and planners rely on flood hazard maps to identify areas at risk of being submerged in river floods. However, floodwater scouring of the land beneath roads, bridges and buildings causes the most damage during floods in steep river valleys, and current flood hazard maps need to be updated to account for this risk. Furthermore, communities affected by recent floods have enacted various measures to reduce the damage from future floods, but it is unclear which of these measures are most effective in hilly and mountainous regions. Developing effective solutions to these problems requires close partnerships between scientists, communities most impacted by river floods, and professionals engaged in flood hazard planning. In this two-year project, three workshops are convened to build and strengthen partnerships, collect information about recent floods, and identify the most pressing research questions related to river flooding. The research team includes undergraduate and postdoctoral researchers. Data products and analysis are provided to communities to aid in decision-making and planning. This project has four goals: (1) strengthen partnerships and develop relationships with community organizations relevant to river flood hazards; (2) co-develop with community partners a suite of critical research questions in the broad areas of flood erosion hazards, flood adaptation solutions, and implementation challenges; (3) develop a database of flood erosion impacts and flood adaptation measures for local communities; and (4) identify effective strategies for sharing climate and flood data with communities. This project uses a Community-Based Participatory Research (CBPR) approach to build equitable community partnerships, and involves the participation from community members, organizations representing those most vulnerable to flooding, and actors engaged in flood hazard planning. 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 · 2024-09

SUMMARY/ABSTRACT Pseudomonas aeruginosa is a major respiratory pathogen in the pathogenesis of Cystic Fibrosis (CF) and the ineffective immune response to this pathogen is thought to cause the majority of the lung damage characteristic of this disease. In the later stages of CF, P. aeruginosa reside in biofilm communities in the lung, accounting for their resistance to antibiotic therapies. To date, little is known about host factors that promote the transition of P. aeruginosa from acute to chronic infection in CF. CF patients show a reduced ability to clear P. aeruginosa acquired during respiratory viral infections and frequently new pseudomonal colonization in people with CF follows a respiratory viral infection. We have shown that virus co-infection, and the subsequent antiviral interferon response, promote biofilm conversion by P. aeruginosa. Interferon has potent antiviral activity, but in addition, interferon stimulated gene (ISG) effector functions have been reported to promote pathogen replication, suggesting that pathogens have evolved to subvert and even benefit from the interferon response. Decades of research demonstrate metabolic reprogramming as part of the host response to acute viral infections, with induction of aerobic glycolysis being a common observation. Our preliminary data suggest that the innate antiviral immune response through IFN signaling induces aerobic glycolysis during RSV infection, while still maintaining oxidative phosphorylation in the respiratory epithelium. Using an improved model to culture P. aeruginosa biofilms in association with human CF airway epithelial cells and a RSV mouse infection model, we will examine mechanisms by which antiviral interferon signaling promotes biofilm conversion by P. aeruginosa through a mechanism of metabolic reprogramming. To this end, we will determine how metabolic reprogramming of the respiratory epithelium facilitates viral-bacterial co-infection, define how secreted metabolic products from the virus-infected respiratory epithelium promote P. aeruginosa persistence and chronic infection by impairing antibacterial function in recruited macrophages and promoting bacterial biofilm growth. Our goal is to elucidate the molecular mechanism for virus-stimulated bacterial biofilms and thus, identify new targets that could delay acquisition and chronic bacterial colonization, or work in conjunction with existing therapies, to eradicate P. aeruginosa in CF patients.

NSF Awards · FY 2024 · 2024-09

Estimates of the magnitude of sea-level rise largely come from computer models that predict ice-sheet behavior. For these models to accurately predict sea-level rise, physical ice-sheet processes must be properly represented. Accurate predictions of ice-sheet behavior and the magnitude of sea-level rise are critical for decision makers. This project will simulate the complete disappearance of the Laurentide Ice Sheet that once covered much of North America. The retreat of the Laurentide Ice Sheet that began about 20,000 years ago presents a natural test case to better understand 1) the physical driving mechanisms that result in the complete disappearance of an ice sheet, and 2) the rate at which an ice sheet disappears. Lessons learned from this research will provide key insights into how large-scale ice-sheet retreat occurs which has clear relevance for predicting the future evolution of Earth’s vulnerable extant ice masses, such as the Greenland and West Antarctic ice sheets. A key question in ice-sheet science is determining how the influence of dynamic mass loss changes through time for a retreating ice sheet and what might control this variability. Lessons from prior episodes of ice-sheet retreat in the geologic record can elucidate how the role of dynamic mass loss changes with time in a fluctuating climate and improve ice-sheet model performance. The researchers will use the next-generation state-of-the-art Ice Sheet System and Sea-level Model (ISSM) to explore the disappearance of the Laurentide Ice Sheet over the last 20,000+ years. In a first-of-its-kind application, ISSM will be used at a spatial resolution capable of capturing large-scale ice-streaming and ice discharge through narrow fjords, along with implementation of coupled solid-Earth-sea-level feedbacks to investigate the role of dynamic ice discharge in driving the disappearance of the Laurentide Ice Sheet. To test model performance, the researchers will compare simulations of Laurentide Ice Sheet retreat against both existing and new geologic benchmarks generated over the course of this project. This project will provide the first quantitative estimates of how the percentage of dynamic mass loss versus surface mass balance evolved over the course of a full deglacial sequence and how this evolution influenced the fate of the Laurentide Ice Sheet. The project will develop a new collaboration with California State University, Long Beach, which is a designated minority serving institution, to recruit students from the Los Angeles area for internships at NASA’s Jet Propulsion Laboratory by leveraging an existing program. 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 · 2024-09

Ni-based superalloys were developed in the 1940s and have been continuously improved ever since, culminating in the current single-crystal jet turbine blades made by directional solidification. However, the cost of such turbine blades exceeds $15,000 and replacement costs when a jet engine is overhauled can be hundreds of thousands to millions of dollars. Thus, a cost-effective method of producing Ni-based superalloy turbine blades is imperative. This award supports research into methods to produce columnar-grained structures or single crystals of nickel alloys by directional recrystallization (DR), a solid-state process, of additively manufactured (AM) material, in which the complex structures are built layer-by-layer by powder fusion. The goal is to investigate if production of a single crystal Ni-based superalloy turbine blade is feasible via the integrated route of AM and DR, and to understand the physics underlying such a processing route. The technology, although focused on Ni alloys, is nonspecific and could be used for other materials, and easily scaled up. The project will train undergraduates and Ph.D. students. In addition, undergraduates from Smith College and from the University of Massachusetts will undertake an annual workshop on AM technology. To gain a fundamental understanding of DR processing of AM materials, the project will use several printing strategies to make different AM microstructures using laser powder bed fusion and laser directed energy deposition of Ni-Al alloys, and the microstructures before and after DR processing will be characterized. The project will build a new DR system specifically for this purpose. Several scientific questions will be addressed: (1) Are carbides or similar insoluble particles necessary to prevent equiaxed grain growth and thus enable columnar-grained structures to grow? (2) Are the columnar structures produced by primary recrystallization or secondary recrystallization? (3) Can this technology grow columnar grains or single crystals at high hot-zone velocities? Previous work has indicated that the upper hot zone velocity to propagate columnar grains is substantially higher than that required to nucleate them. (4) Can this technology use a spiral growth selector built into an AM sample to provide grain selection during DR to produce single crystals? (5) Can single crystals or columnar-grained structures with complex geometries, such as hollow components used for air-cooled Ni-based superalloy turbine blades, be produced by the integrated approach of AM and DR? If successful, this project can generate new understanding in the manufacturing of high-performance alloys, which will advance aerospace industries and alloy manufacturing. 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 · 2024-09

ABSTRACT Pseudomonas aeruginosa (Pa) frequently co-infects with other bacterial and fungal species. For example, 50% of adults with cystic fibrosis (CF) are chronically infected with Pa and Candida albicans (Ca) commonly co- infects. Antagonistic interactions between Pa and Ca can enhance the growth and virulence of both species, resulting in worse clinical outcomes. We found that the sensor kinase CbrA, which is known to regulate carbon catabolite repression and Pa metabolism, is necessary for Pa antagonism of Ca. This is in part through its control of the transcription factor PhoB which we have shown regulates the production of toxins with antifungal activity. Both CbrA and PhoB have been independently implicated in Pa fitness and virulence, but this work is the first that connects these two important regulators. We have also shown that a subset of clinical isolates that are associated with worse clinical outcomes and increased antagonism toward Ca have elevated CbrA activity and CbrA-mediated activation of PhoB. Understanding the mechanism of CbrA activation and its role in Ca antagonism will shed light on Pa polymicrobial interactions as well as in virulent clinical isolates. We propose that CbrA activity is mediated via the conserved Per-Arnt-Sim (PAS) domain via a redox-active small molecule ligand and the candidate will use genetic and biochemical approaches to test this model in Aim 1. As CbrA is conserved across other bacterial species, this will provide insight into similar regulatory pathways. In Aim 2, the candidate will investigate the role of CbrA and phosphate availability in PhoB-mediated Pa antagonism of Ca. Because PhoB activity is also controlled by extracellular phosphate concentrations, the candidate will examine the CbrA-PhoB relationship at physiological phosphate concentrations as well as the high phosphate concentrations present in many laboratory media. This candidate plans to pursue a career in academia in the area of microbial interactions in microbial communities. This work will be supported by several collaborations with biochemists and metabolomics experts, provide the candidate experience working with both a bacterium (Pa) and a fungus (Ca), and establish collaborations in critical areas including metabolite analyses and mentor relationships with researchers in the field. This project will provide opportunities for the candidate to develop their scientific and professional skills and advance their career in research.