California Institute Of Technology

NIH Research Projects · FY 2025 · 2025-08

Fluorescent biosensors and microscopes can measure voltage, calcium, neurotransmitters, and other essential endogenous or exogenous biomarkers. The standard practice is to record the change in biosensor fluorescence intensity over time. The signal can be affected by fluctuations in sensor levels between cells and animals, laser power, imaging position, and other unavoidable experimental factors. Time-resolved fluorescence (TRF) and fluorescence lifetime imaging (FLIM) solve this problem by measuring lifetime instead of intensity. TRF allows well-calibrated measurements of biosensor analyte levels by being resistant to intensity fluctuations. TRF also enables new measurement modalities based on the fluorophore’s local environment, ranging from endogenous fluorescence signals to the near-endless continuum of exogenous FRET and lifetime-based biomarkers. However, portable implementation of lifetime-based approaches is hampered by a pulsed laser’s cost, physical size, power draw, and required domain-specific expertise. The proposal uses integrated photonics to create entangled photon sources that enable highly multiplexed, low-cost, low-power, and portable measurement of TRF/FLIM in a universal package. The Cushing lab has discovered that creating entangled photons with integrated photonics can be used for fluorescence lifetime measurements with both quantum and practical advantages. The advantages include improved tuning range (>500 nm) per source, temporal resolution (< 0.1 ps), a CW-like approach that reduces phototoxicity effects, alignment-free operation through a photonic back end, and <1 cm2 physical size – all powered by the equivalent of a mW laser pointer. Entangled TRF, therefore, appears ideal for portable or wearable, miniaturized TRF and FLIM approaches. The technology can be compared to emerging LED-based miniaturized devices, which lack the ability for high wavelength multiplexing without multiple sources nor the time resolution to distinguish multiple biomarkers and their environmental response. By starting with a CMOS-cost-scalable package using thin film photonics, our innovation will significantly improve health equity by making TRF and FLIM accessible to a broader range of biological and medical researchers. The specific aims of the proposal include 1) optimizing the entangled photon source for excitation- wavelength and temporally multiplexed fluorescence lifetime sensing, 2) extending entangled TRF toward shorter wavelength excitations by transitioning from lithium niobate to lithium tantalate, and 3) integrating on-chip photonic elements for a miniaturized TRF architecture. Collaborators specializing in FLIM and TRF biosensors evaluate each stage of the grant with regard to application, including testing in their labs, to ensure realistic criteria are used in addition to photonic metrics. The proposed research is the first step towards a multiplexed platform that brings TRF and FLIM to broader health applications, including portable medical diagnostics and in-vivo or miniaturized sensors, all using the cost scaling of integrated photonics.

NIH Research Projects · FY 2025 · 2025-08

Proposal Summary/Abstract Antibody (Ab) Fc-mediated effector functions are an important correlate of protection against viral pathogens such as SARS-2. Methods such as systems serology are used to evaluate what kind of effector responses are protective for Abs against SARS-2 and other viruses, though crucial information about the epitope specificity those protective Abs are targeting is missing. To develop the most effective variant-proof or broad vaccines against sarbecoviruses, it is essential to determine which epitope specificities, when combined with Fc effector responses, can offer the most broad and robust protection. In this proposal, I aim to integrate deep mutational scanning (DMS) into systems serology, offering an innovative approach to map the epitope specificities within distinct IgG subclass and FcγR binding compartments of serum obtained from animals immunized with RBD-based protein nanoparticles and SARS-2 mRNA-Spike vaccines. This integration will facilitate the correlation between the binding epitopes of Fab regions in polyclonal Abs and the resulting Fc mediated functional responses. Although it is typically assumed there is no connection between the epitope specificity and the Fc subclass, preliminary findings surprisingly indicate variations in epitope specificity across different subclass compartments within the serum response, implying potential functional implications. The proposal will further involve the profiling of Ab-secreting cells at the single cell level to explore antigen specificity, IgG subclass, and FcγR binding properties, enabling the isolation and characterization of monoclonal antibodies (mAbs) with diverse antigen breadth and Fc characteristics. This multifaceted analysis will unveil patterns in epitope specificity and Fc properties at the monoclonal level. Finally, the project will assess the protective efficacy of serum and mAbs with distinct epitope specificity/Fc properties against homologous and heterologous SARS-2 infections, shedding light on the influence of epitope-specific Fab binding on Fc-mediated protection. Altogether, this proposal will make it possible to design immunization strategies that can more precisely modulate both Ab targeting and functional responses elicited, which will allow for a new generation of broadly protective vaccines. The mentoring phase of my proposal will take place in the lab of Dr. Pamela Bjorkman at Caltech. I will be advised by and collaborate with Dr. Jesse Bloom for DMS, Dr. Galit Alter for systems serology, and Dr. Mike Diamond for protection studies, gaining additional training required for this proposal. The research and mentorship proposed here will support me in reaching my overall career goal to establish my own academic research lab, with a focus on understanding the basic immunology of Abs targeting of viruses and designing better viral vaccines and therapeutics.

NSF Awards · FY 2025 · 2025-07

This award supports student travel and registration expenses for the 31st International Conference on DNA Computing and Molecular Programming (DNA31), which will take place August 25-29, 2025 at the École Normale Supérieure de Lyon, France. This support will give a new generation of molecular programming researchers the opportunity to present their work and interact with students from other institutions and senior researchers in the field. This highly interdisciplinary conference emphasizes topics that bridge computation, biology, and nanotechnology and attracts top researchers in the fields of computer science, mathematics, chemistry, molecular biology, and nanotechnology. The scope of topics for contributed talks include control of molecular folding and self-assembly of nano- and micro-structures; demonstration of biomolecular switches and circuits that process chemical information in vitro and in cells; molecular motors and molecular robots; studies of fault-tolerance and error correction in molecular self-assembly and molecular computation; synthetic biology and molecular evolution; DNA data storage; and software tools for analysis, simulation, and design of molecular structures and circuits. These topics have applications spanning engineering, physics, chemistry, biology, medicine, and education. Conference organizers will support the travel of up to 25 students who are either US citizens or enrolled at US institutions to travel to DNA31. Students who plan to present their work at the conference, especially students from institutions that would otherwise be unable to afford conference attendance and trainees in molecular computing research who might not otherwise have the opportunity, will be prioritized for awards. Requests for student applications will be circulated in regular conference announcements, and a committee of conference organizers will make selections from the received applications. The awards will support registration, travel, and accommodations for students. The availability of this support will foster broader conference attendance and help advance human knowledge and develop new technologies. 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 2025 · 2025-06

With the support of the Chemical Synthesis (SYN) program in the Division of Chemistry, Professor Sarah Reisman of Caltech is studying the development of new catalytic reactions for the chemical synthesis of natural products. Natural products are molecules isolated from natural sources, which often serve as promising lead compounds for the discovery of new medicines or agrochemicals. The ability to synthesize these molecules in the laboratory can allow chemists to precisely modify their structure, study how the molecular structure affects function (e.g. biological activity), and design new molecules with improved properties. These synthetic efforts are enabled by fundamental studies aimed at developing new chemical reactions, particularly those that form carbon–carbon bonds. The experimental research seeks to develop new catalytic reactions that enable the efficient synthesis of the natural product enterocin. Although the proposed efforts will focus on enterocin, the broader impact of these studies will be to provide new general chemical reactions and strategies that can be used to synthesize related molecules of interest for applications in medicine and beyond. The rigorous training of scientists in the theory, methods, and strategies of synthesizing organic molecules will be an essential part of the funded research studies. Undergraduate, graduate student and post-doctoral researchers trained through this research experience will be poised to pursue careers in the chemical, pharmaceutical, agrochemical, biotechnology, and materials science industries. With support from the Caltech Center for Teaching, Learning and Outreach (CTLO), the Reisman team will participate in outreach programs that help students from local community colleges prepare for transfer opportunities and competitive undergraduate research programs by obtaining mentorship from Caltech graduate students. Structurally complex natural products – which often possess sterically congested three-dimensional topology and multiple reactive functional groups – challenge the limits of current synthetic methodology. This award will support the development of a radical-polar crossover annulation (RPCA) using photoredox catalysis to prepare the bridging bicyclo[3.2.1]octane core of the polyketide enterocin. Several approaches are proposed to elaborate from the RPCA product to enterocin, including the use of C–H functionalization. This work will also investigate the application of this radical-polar crossover annulation as a scaffold transposition method to access carbocycles from lactones. It is expected that these studies will advance the state of the art in catalytic C–C bond formation and demonstrate how modern synthetic methods can improve synthetic strategies. 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 2025 · 2025-06

Galaxies are made of stars, gas, and black holes. The interaction between these components determines how a galaxy, like our own Milky Way, grows over time. Stars and black holes may change the chemical content of the gas reservoir and/or eject it completely out of the galaxy through winds. The latter outcome, particularly prevalent in interacting galaxy systems, tends to stop future generations of stars from being formed in those galaxies. The investigators will analyze new observations of merging galaxies to trace the movement of gas as it traverses the galactic ecosystem, enabling a detailed understanding of this dynamic process. The investigators will also augment the Observational Astronomy Workshop at Lick Observatory through increasing graduate student participation and by adding a new science communication module to enrich the education and professional development of a diverse range of students. Leveraging new Keck and JWST integral-field spectroscopic observations, the investigators will study the hot ionized and warm molecular gas for a representative sample of galaxy mergers to establish the intricate nature of gas fueling and feedback and its role in galaxy evolution. Outflowing gas masses and energetics will be measured and compared to predictions from the latest feedback models across the temperature--density regimes. Presenting a holistic view of gas dynamics from the dusty nuclear cores out to the circumgalactic medium, this project is extremely timely. 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 2025 · 2025-05

Carbon isotopes serve as important tracers of metabolism in both the biological and earth sciences. Earth scientists have long used subtle variations in the natural abundance of the stable isotope carbon-13 in biomolecules to draw inferences about organismal or biochemical origins, and metabolic carbon fluxes. In systems biology, the metabolomics approach employs the addition of carbon-13 tracers to cultures, followed by monitoring of labeled metabolites to quantify carbon fluxes through metabolic pathways. However, a key drawback is that this approach is only feasible for organisms cultivated in the lab, where relatively high levels of isotope tracer can be achieved. Similar information is potentially available in the natural-abundance distribution of carbon isotopes, as they are modulated by kinetic isotope effects that accompany most metabolic reactions. Retrieving this information requires a specialized style of mass spectrometry that is already available in isotope geochemistry labs; as well as new metabolic models that account for all of the relevant fluxes and isotope effects. The latter is tractable but as-yet unproven. This project will leverage the unique collaboration between an isotope geochemist (at Caltech) and a systems biologist (at Northwestern) to combine these two approaches to develop and validate a new algorithm for measuring rates and types of metabolism in organisms, based on natural abundances of the carbon-13 isotope. The goal of this project is to build and validate the newly developed algorithm for aerobic and anaerobic heterotrophic bacteria, using both conventional (13C-tracer) and natural-abundance measurements as constraints. The success of this project would greatly expand our ability to quantify metabolic fluxes in organisms collected from the environment, as well as to predict their stable isotope signatures. This new ability could have many important applications, including improved understanding of how many microbes function in the environment, as well as marine and soil food webs, fisheries, and the carbon cycle. The project will provide training of graduate students at Caltech and Northwestern, and involve the partnerships of respective institutions with educational activities with local middle-school and high-school students. 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 2025 · 2025-05

This CAREER award will investigate how bacteria move in porous environments such as tissue, gels, soils, and sediment. Bacteria are examples of microswimmers, a class of particles that can propel themselves through fluid. The investigators will use 3D printing to fabricate porous environments with controlled pore structures, and they will use microscopy to observe how the bacteria move. These studies will reveal how the motion and self-organization of bacteria depend on the properties of their environment, the properties of the cells themselves, and interactions among the cells. The project will provide new research experiences and educational modules for high school, undergraduate, and graduate students, with a specific focus on students from under-represented groups. It will also enable new presentations and demonstrations to inspire and engage K-12 students at the Princeton Public Library and at local schools. Finally, it will provide opportunities for discussion forums, workshops, and dissemination of computational tools to the broader scientific community. This project will develop new experimental techniques and mathematical models to generate a fundamental understanding of microswimmer transport and collective behavior in porous media. The work will focus on bacteria, an archetype of microswimmers that can move through fluid by flagellar propulsion. Two fundamental questions will be addressed. First, how is single-cell motility altered by pore-scale confinement - specifically, how does motility depend on the properties of the cells and of the porous medium? Second, how do cell-cell interactions guide collective behavior in porous media? By connecting cellular properties, porous medium properties, and motility/collective behavior, this work will generate knowledge to enable prediction and control over bacterial transport and organization. Results from this project will help practitioners control bacterial behavior in applications such as treating infections, microbial drug delivery, using soil bacteria for agriculture, and bioremediation. More broadly, this work will provide a foundation for future studies of microswimmers in complex environments and will guide the design and use of synthetic microswimmers for applications ranging from drug delivery to chemical sensing. 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 · 2025-04

Leveraging computationally derived measures of individual differences in learning and decision-making to predict psychiatric diagnosis, symptoms and changes in symptom severity across time. PI: John P. O’Doherty PROJECT SUMMARY The goal of computational psychiatry is to gain knowledge about underlying neurocomputational processes that underpin psychiatric disorders and to leverage this knowledge for improving diagnosis and treatment. A key step toward achieving this goal is to develop measures of individual differences in computations obtained from a single individual that are reliable, robust and meaningfully relevant to psychiatric dysfunction. In order to attain these objectives, it is essential we substantiate relationships between candidate computational mechanisms and diagnostic categories, symptom dimensions and treatment outcomes. In the present proposal, we utilize a computational assessment task battery (CAB), designed to measure individual differences across a multidimensional array of computational processes. We aim to separate three different variance components contributing to variability in computational parameter estimation: occasion-related variance due to incidental day to day changes in task performance, state-dependent variance that is related to meaningful variation across time in the underlying computations within an individual, and trait-related differences pertaining to stable individual differences in computations across individuals. To accomplish this, we will first implement repeated assessments using this battery across a 1-year interval within an on-line sample, and use hierarchical Bayesian modeling to separate the effect of occasion, state and trait-related variance on these parameter estimates. We will then relate these variance components to diagnostic categories, symptom dimensions and symptom severity measures in a diverse cohort of psychiatric patients (mostly with depression, anxiety and OCD) recruited in Southern California. Finally, we will track the relationship between the computational parameter estimates and changes in symptoms across time in a subset of these patients. We hypothesize that overall diagnosis will be best predicted by trait variance components, while current symptom severity will more closely relate to state-related variance in parameter estimates. Our proposal promises to significantly advance understanding of how to reliably extract diagnostically relevant computationally-derived measures of cognitive phenotypes that could eventually be migrated to the clinic.

NSF Awards · FY 2025 · 2025-04

The Conference on Foundations of Nanoscience meeting (FNANO) is an annual conference focusing on key topics in nanoscience including experimental and theoretical studies of self-assembled architectures and devices, at scales ranging from nano-scale to meso-scale. The conference spans traditional disciplines including chemistry, biochemistry, materials, physics, computer science, mathematics, and various engineering disciplines. This award will provide travel support to 25 students and postdoctoral fellows from US institutions to attend the twenty second annual conference on Foundations of Nanoscience (FNANO25), including students and fellows from historically underrepresented groups. Cross-disciplinary interactions are crucial for the advancement of nanoscience, but often work that is published in one area is not readily accessible to researchers in another area. FNANO was established as a venue for fostering such interactions between individual researchers interested in various aspects of self-assembly. By bringing top researchers in self-assembling nanostructures together in a stimulating environment, with an emphasis on breaking results and discussion, the conference helps researchers communicate new ideas and techniques swiftly and form research collaborations. The support from NSF will significantly enhance interdisciplinary basic research in the area of nanoscience and allow researchers to initiate and maintain cross-discipline collaborations. It will encourage trainees to attend the conference and interact with active and leading researchers in the field of nanoscience and nanotechnology. 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 · 2025-04

PROJECT SUMMARY The cranial neural crest (NC) contributes to the formation of many craniofacial structures including the bones and cartilage of the face, tooth dentin, peripheral ganglia, and the meninges. In the context of craniofacial biology, the cranial meninges provide osteogenic signals, instruct calvarial patterning, and morphogenesis, maintain cranial suture patency, and act as stem cell reservoirs, essentially regulating the development of these structures. During early embryogenesis, mesenchyme cells derived from the NC and mesoderm surround the brain and establish a mesenchymal sheath, the primitive meninx, which serves as the primordium for the meninges, skull, and scalp. The primitive meninx will eventually form the tri-layered meningeal structure – dura, arachnoid, and pia mater. In amniotes, the cranial NC gives rise to the forebrain's meninges, whereas the midbrain and hindbrain meninges are mesoderm-derived. Unfortunately, the gene regulatory networks (GRNs) deployed for early meningeal development and why the dichotomy exists in the case of meninges origin are poorly understood. Defects in NC development lead disorders, termed “neurocristopathies”, that include Treacher Collins syndrome, craniosynostosis, 3MC syndrome, Meckel-Gruber syndrome, and Pfeiffer syndrome which present with improperly/abnormally fused skulls and incompletely formed skulls. Whether these defects arise as a result of improperly formed meninges is still underexplored. Moreover, abnormal proliferation of meninges sporadically or due to cranial radiotherapy and genetic disorder Neurofibromatosis type II can lead to the formation of pediatric and adult meningiomas. My preliminary studies have identified that NC/mesoderm origins of the meninges are conserved in zebrafish and developed an inducible meningioma model. With this Pathway to Independence Award, I will seek to explore and understand the underlying mechanisms of meningeal development and tumorigenesis. The overall objectives of this proposal are to dissect the spatiotemporal heterogeneity and plasticity of the cranial meninges using single-cell (sc)-multi-omics, whole animal live imaging, and tissue-specific ablation (Aim1), functionally characterize the GRNs involved in meningeal development (Aim2), and determine the developmental GRNs activated in cranial meningiomas (Aim3). The work proposed in this Pathway to Independence Award proposal will be greatly facilitated by my multi-disciplinary advisory committee with expertise in single-cell RNA-seq approaches/analyses, functional genomics, and live imaging. After developing a formidable skillset and research foundation afforded by the two years of the mentored phase of this award in Dr. Marianne Bronner’s lab at the California Institute of Technology, my goal is to establish a high-impact, independent research group that will combine systems-level approaches with state-of-the-art cell and developmental biology techniques to address questions of tumorigenesis through a developmental lens. Long- term project hypotheses are focused on delineating tissue-level interactions between the meninges and the skull during development and tumorigenesis.

NSF Awards · FY 2025 · 2025-03

The formation and sinking of organic particles into the deep ocean are important processes in global element cycles. These particles (also called ‘particulate organic matter’ or POM) carry carbon into the deep ocean where it is stored for hundreds of years. The storage of carbon in the deep ocean contributes to the drawdown of atmospheric carbon dioxide as well as loss of nutrients from the surface ocean. Understanding the mechanisms and processes that govern the fluxes of POM is thus directly relevant to the global carbon cycle, marine ecology, and fisheries. This project uses new tools to measure the isotopes of three different elements (hydrogen, carbon, nitrogen). The approach shows promise for addressing a long-standing question: to what extent do bacteria replace the organic matter from algae (the original source of the POM) as particles sink. Results from this study will be important for predicting the amount and dietary quality of POM in a rapidly changing ocean. The project will support Ph.D. students at both Caltech and University of Miami and educational activities for K-12 and college students. The project takes advantage of a recent analytical development, the measurement of hydrogen isotopes in amino acids as a new tracer. Preliminary measurements suggest that there is a large (up to 20%) shift in the hydrogen isotope ratio of amino acids within POM over the upper 300 m of the ocean, consistent with the depth at which POM degradation is most intense. The investigators hypothesize that the shift in hydrogen isotopes reflects the replacement of phytoplankton biomass with bacterial biomass. The project will test this hypothesis through 1) the analysis of archived POM samples from four different localities in the Atlantic and Pacific oceans, 2) measurements of diverse phytoplankton grown in culture, and 3) degradation experiments in which algal biomass is fed to bacteria and zooplankton. In addition to cutting-edge hydrogen isotope measurements, the investigators will employ a suite of additional measurements to characterize the microbial communities and POM being studied. Collectively, this work aims to develop hydrogen isotopes in amino acids as a novel proxy for the turnover of organic matter within marine particles, which could be applied to studies of marine POM throughout the world’s oceans. The project will also develop outreach activities to introduce K-12 and collegiate students to marine science. These will be implemented through the GO-Outdoors program in Pasadena, the Exploring Marine Science Day in Miami, and undergraduate student cruises in Miami. 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 2025 · 2025-03

This project aims to develop a detailed 3D model of the Los Angeles (LA) Basin, critical for accurately estimating earthquake ground motion and assessing seismic hazard for this densely populated area. The LA metropolitan area sits above a deep sedimentary basin that significantly affects the level of ground shaking from local and regional earthquakes. The basin has a complex tectonic history of extension and compression and is also crosscut by numerous faults. This has resulted in a complicated subsurface structure that leads to significant variation in site amplification of seismic waves across the basin, as evidenced by the recorded ground shaking following the 2019 Ridgecrest earthquake. In the summer of 2022, a temporary 300-node geophone array was deployed across the entire LA basin, providing a seismic data set with uniform and dense coverage for the first time. In this project, the researchers will analyze these data and combine them with other available seismic and gravity observations in the region to construct a detailed 3D basin model. The model will help explain the level of amplification in different areas of the basin as well as its lateral variations The resulting model may be used to model ground motion for realistic earthquake scenarios, which is vital for evaluating infrastructure preparedness. In addition, this project will explore the connection between the resulting seismic velocity model with mapped geological features, and the tectonic evolution of the LA Basin. Through the research, the project will support graduate and postdoctoral education, and the scientific findings will contribute to seismic hazard assessment efforts in southern California. The density of the 300 sensor LA nodal array deployed in 2022 will enable the use of novel passive seismic imaging methods. By extracting Rayleigh and Love surface waves from multi-component ambient noise correlations, it will be possible to measure their velocity dispersion and Rayleigh wave ellipticity in the region. Techniques based on particle motion and apparent slowness will be developed to isolate different modes of surface waves. Both isotropic as well as radially and azimuthally anisotropic basin structures will be investigated using surface wave measurements. By using receiver function and autocorrelation methods, in addition to surface wave properties, it will be possible to determine crustal discontinuities, including major intra-basin sedimentary interfaces, the bottom of the basin, and the shape of the Moho beneath it. The use of gravity data will guide the identification of converted and reflected phases and determine the tectonic extension that the basin has experienced, enabling evaluation of the extent of thermal subsidence that has occurred within it. The dataset that will be analyzed is unique in an academic setting for its density, regularity, and completeness of coverage, allowing for the exploration of new methodologies. These include mapping shallow seismicity to identify possible unknown faults, using reflected surface waves to map the properties of faults within the basin as well as discover new ones, and determining aspects of the stress field through anisotropy. The 3D basin model constructed in this project is expected to be more accurate than the current community velocity models (CVMs), enabling more reliable ground motion predictions for various earthquake rupture scenarios. The new model will be validated through simulations of recent earthquakes. 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 · 2025-02

SUMMARY Transcriptomics generates massive amounts of data that we aim to physiologically interpret in terms of how cells respond to different conditions by regulating activity levels of pathways. Curators encode our knowledge in pathway databases like KEGG, Reactome, and, more recently, GO Causal Activity Models (GO-CAMs) to provide detailed qualitative depictions of pathways, but a major component of our knowledge is missing – a description of how gene expression varies as a pathway is differentially regulated by cells. For example, when glycolysis is differentially regulated, is it always the same subset of genes that are turned up or down? Knowing which genes vary together (or are uninformative) and having the context of the range of gene expression across cell types and in response to conditions would be invaluable, because then we would know which genes are informative and which to ignore to determine if a pathway is up or down regulated. This begs the question: Can the diversity of cell types or the responses of cells to various conditions be described by differential regulation of pathways instead differential expression of 20,000 genes? If so, this could allow us to infer physiology of cell types and the regulation of pathways by studying patterns of gene coordination within them. This project will use human single cell RNAseq atlases and GO-CAM pathway models to test the hypothesis that gene expression within pathways is coordinated in a stereotyped manner and that these coordination strategies are largely shared even by cell types but differentially tuned. To develop scoring metrics and references for transcriptional regulation of pathways, within each pathway, the genes’ whose expression levels are most informative of that pathway’s regulatory state will be identified through Weighted Gene Correlation Network Analysis. This may have tissue or cell type specificity, so an extension of k-means clustering to k-affine subspaces (i.e. points, lines, and planes in 3D) will be used to model subpopulations that coordinate gene expression differently, and cell type labels will be used to understand how gene expression is scaled along these subspaces by different cell types. These results will be made available as a database and tool. Lastly, experimentalists interpret their RNAseq results by considering the molecular function (MF) identities of pathway steps (i.e. receptors, enzymes, intracellular messengers). To determine whether such a high-level logic exists across pathways, the integration of GO-CAMs with the GO will be used to determine if MF or the type of causal edge between steps influences transcriptional co-regulation. These aims will advance our understanding of how gene expression is coordinated within pathways, how this is specific to or shared by cell types, and whether motifs for transcriptional regulation are shared across pathways. Together, these will improve our ability to interpret RNAseq data in a physiologically meaningful manner.

NIH Research Projects · FY 2026 · 2025-01

Project Summary The proline-rich homeobox protein Hhex is important in hematopoiesis, in embryonic development, and in cancer. A critical regulator of early embryonic hematopoiesis and other embryonic tissues, it is also known to be required for hematopoietic stem cells to maintain the ability to give rise to T and B cell progeny. It is intimately involved in several aspects of B cell development, and it is crucial for establishment of memory B cells. However, how it enables stem cells to produce T cells has remained unclear and paradoxical. Normally, Hhex is silenced during T cell lineage commitment and remains off in most mature T cells, sharply distinguishing T cells from nearly all other hematopoietic cell types. Yet not only is Hhex needed to support T lineage potential, but also forced expression of Hhex in T lineage cells can promote increased thymocyte self- renewal. Is its role positive or negative, or both sequentially? We propose that in fact Hhex roles can be reconciled as results of the need of early T-cell precursors to pass through a “phase 1” progenitor-like regulatory state en route to a “phase 2” T-lineage-definitive regulatory state, even though these states are mutually antagonistic. Our recent results show that Hhex at natural endogenous levels is a potent regulator of T lineage differentiation speed, and suggest that it may initially delay the onset of commitment by repressing a key T-lineage commitment regulator, Bcl11b. The role of Hhex in Bcl11b regulation could provide much-needed insight into a control mechanism for large-scale epigenetic transformation in development. Unexpectedly, our preliminary evidence also suggests that Hhex positively regulates other factors expressed in the precommitment stage. This proposal thus grows from new data from our group and exploits newly enhanced experimental systems that enable us to interrogate the functions of transcription factors like Hhex, targeting specific stages from prethymic hematopoietic progenitors through T- lineage commitment. This will empower us to reveal the specific target genes and mechanisms that Hhex uses to control them when it is operating properly in T-cell precursors. This will be undertaken through the following aims: 1. Determine the target genes in early T lineage cells affected by acute loss of Hhex: separate analyses for cells pre and post contact with T-inductive Notch signaling microenvironment 2. Quantify the impact of Hhex on cell population survival and proliferation before and after contact with Notch signaling and lineage commitment 3. Define Hhex functional targeting sites based on binding of epitope-tagged Hhex, and on ATAC accessibility, H3K27 trimethylation, and TLE corepressor recruitment changes in early T lineage cells under acute Hhex perturbation. Identify Hhex impact on chromatin of the Bcl11b gene

NIH Research Projects · FY 2024 · 2025-01

Project Summary/Abstract There is a growing consensus that men and women differ in their response to kidney injury, and their susceptibility and progression to chronic kidney disease. Similar findings have come from the analysis of different sexes in rodent models. Historically, females have been under-represented in animal modeling and clinical studies. Redressing this imbalance and understanding how sex-related differences in gene expression are generated, and how these influence normal and pathological actions within mammalian organ systems, is a priority. Recent single cell RNA-seq studies in the McMahon group have highlighted extensive sexual dimorphism within proximal tubule segments of the adult mouse kidney. Proximal tubule cells share a major role in chemical modification of circulating metabolites with hepatocytes of the kidney. Proximal tubule cells also have kidney specific actions in resorption, transport and removal of beneficial or harmful molecules. Comparative analysis shows both similar and distinct sexually dimorphic gene sets between the liver and kidney, with potential differences in hormonal interplay (androgens, estrogens, growth hormone) underlying how each organ establishes dimorphic cell states. Pregnancy and nursing present additional demands on the female, specifically. How these demands may impact dimorphic cell states in the female kidney is not clear, even in the mouse model. Due to the absence of comparable, high quality, comparative data for the human kidney, there is no clear idea of the extent of sexual dimorphism in the human kidney, and consequently, which regulatory actions may be shared with mouse models, or are human specific. In this proposal, we will use single nuclear (sn)RNA-seq, snATAC-seq and genetic approaches to determine the regulatory processes establishing sexually dimorphic cell types in the mouse kidney, and those modifying gene activity within proximal tubule cell in the reproductive process. Comparable datasets emerging from worldwide efforts applying single cell technologies to human systems will be co-analyzed for shared and distinct regulatory processes. Specific Aim 1 will determine regulatory mechanisms, including the action of direct hormone signaling (androgens, estrogen and growth hormone), in generating distinct proximal tubule cell types in the male and female mouse kidney. Kidney datasets will be contrasted with similar data for overlapping gene cohorts within sexually dimorphic hepatocytes. Specific Aim 2 will determine the regulatory interplay of pregnancy, nursing and prolactin signaling in modifying sexually dimorphic cell states in the mouse kidney. Specific Aim 3 will compare sexual dimorphism in the mouse with human kidney biopsies, integrating data generated in the proposal into the framework of KidneyCellExplorer (https://cello.shinyapps.io/kidneycellexplorer/) for viewing and analysis of the data.

NSF Awards · FY 2025 · 2025-01

Global sea levels are rising at unprecedented rates and will continue to reshape the coastline of densely populated regions both in the US and globally with implications for housing, transportation, agriculture, wildlife habitability, and tourism. Over the next 50 years, mass loss from the Antarctic Ice Sheet will be a dominant contribution to global sea level, but it is also associated with the greatest uncertainty in sea level rise estimates. Much of this uncertainty results from incomplete understanding of processes that occur near the Antarctic coast where there are close interactions between the open ocean, near-coastal waters whose properties are influenced by interactions with sea-ice, and ocean water that is carrying glacier meltwater originating from the Antarctic ice sheet itself. These regions also happen to be among the most biologically productive of all waters in the Southern Ocean, and the impact of climate-related biogeochemical changes here remain a blind spot in our understanding of a changing global carbon cycle. Current understanding of changes occurring around Antarctica are largely derived from decades of work in the Amundsen Sea. Yet, the melting of ice shelves in the neighboring Bellingshausen Sea are comparably high and pre-condition the physical and biogeochemical properties of the water that enter the Amundsen. Thus, the role of the “upstream” Bellingshausen Sea in ice sheet mass loss and ocean carbon uptake remains unconstrained, although models suggest this region can broadly influence these processes throughout West Antarctica. The Bellingshausen Sea: A Carbon and Overturning Nexus (BEACON) project will collect a broad suite of physical and biogeochemical observations needed to assess the Bellingshausen Sea’s role in the large-scale distributions of heat, meltwater, dissolved iron and other nutrients, and biological productivity. The research team will combine standard and trace-metal shipboard measurements, towed underway observations, and a small fleet of remote autonomous underwater vehicles aimed at capturing key transport pathways associated with narrow boundary currents located along the coast. These observations will capture dynamical processes related to mixing of water properties by ocean turbulence from centimeter to kilometer scales. This information about mixing will then be applied to an inverse-modeling framework to assess how changes in near-coastal processes in the Bellingshausen Sea impact larger-scale ice-shelf melt rates, nutrient supply to the upper ocean, the timing and intensity of seasonal primary production, and the oceanic uptake of carbon dioxide throughout West Antarctica. 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 2025 · 2025-01

Astrophysical sources are now being studied by simultaneously combining information from multiple messengers - gravitational waves, neutrinos and light. Each of these messengers are undergoing improvements in sensitivity by hardware upgrades. Hand-in-hand with hardware progress, urgent software progress is needed. The investigators will develop open-source and accessible software to deliver three major missing software needs. The program includes a real-time Zooniverse for classrooms that leverages longitudinal timezone differences to allow citizen scientists to tune into the excitement of real-time multi-messenger discovery, collaborations with the amateur astronomer community to further their contributions to multi-messenger discoveries, and the organization of a summer internship program for undergraduate and graduate students that is cross-institutional. A 3-year proposal led by the California Institute of Technology spans the breadth of multi-messenger astrophysics, including electromagnetic counterparts to both gravitational wave sources and high energy neutrinos. The investigators propose to deliver three open and accessible software infrastructure projects that will boost discoveries for the entire multi-messenger community. First, enabling joint querying of heterogeneous discovery streams in real-time. This will boost both timely selection of the most viable multi-messenger candidates as well as timely rejection of the false positives. Second, facilitating active follow-up co-ordination between independent teams using a decentralized communications framework. This will enable optimal use of follow-up resources that are already the bottleneck in multi-messenger searches. Third, improving software for public low-latency gravitational wave alerts using inclination-based inference to refine electromagnetic counterpart search strategies. Together, these three software infrastructure pillars will amplify the power of collaborative discovery. 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

PROJECT SUMMARY The growing antibiotic resistance crisis has revived interest in using phage therapy (viruses that infect and lyse bacteria) to treat drug-resistant, pathogenic infections. Despite its promise, current phage therapy development faces significant challenges in scalability and accessibility. Since phages are highly specific to their bacterial hosts, it is difficult for a developed phage therapy to maintain treatment efficacy across various and evolving strains of the same pathogen. This necessitates a continuous search and development of new phages, which is highly time- and resource-intensive. Moreover, phage genomes have evolved to be highly compressed; that is, the same stretch of sequence encodes more than one protein in different reading frames, which severely limits the possibilities for phage genome engineering and reconfiguration. To attain the breakthrough capability to facilitate phage therapy development against any antibiotic-resistant pathogen, this proposal aims to develop an adaptive framework to rapidly synthesize and reconfigure synthetic phages. Specifically, we will decompress phage genomes into physically distinct open reading frames using in vitro genome assembly and synthesize decompressed phages using the E. coli cell-free system. This innovative approach will create modular phage genomes compatible with interchangeable parts and a generalizable expression platform for on-demand phage synthesis. During the mentored phase (K99) of this award, we will optimize the E. coli cell-free system to produce phages that infect Pseudomonas hosts, which are evolutionarily distant from E. coli, demonstrating this platform’s capacity to synthesize phages against a broad range of pathogens (Aim 1). In addition, we will decompress existing Pseudomonas phage genomes into distinct reading frames using in vitro genome assembly and will synthesize decompressed phages in the E. coli cell-free system (Aim 2). In the independent phase (R00), we will demonstrate the framework’s adaptability with (1) multiplexed phage genome engineering to develop phage therapy against antibiotic-resistant Pseudomonas aeruginosa, (2) cross-order phage reconfiguration to target gram-negative pathogens, and (3) extending this platform to gram-positive pathogens (Aim 3). The expected outcome of this work is a transformative, adaptive framework to synthesize and reconfigure synthetic phages against existing and emerging pathogens. This contribution is expected to be significant because it promises to transform current phage therapy from a time- and resource-intensive endeavor into a widely accessible treatment option, providing a breakthrough capability to protect public health against existing and emerging pathogens.

NSF Awards · FY 2024 · 2024-12

NON-TECHNICAL ABSTRACT When heated, all materials change their volume, and the celebrated discovery of the low thermal expansion of Fe65Ni35 "Invar" led to a Nobel prize. Only recently has this Invar behavior become understood as a delicate competition between atom vibrations and magnetic spins in the material. This competition likely occurs in all magnetic materials. Besides competing, vibrations and spins can influence each other through "spin-phonon interactions." There is some evidence that spin-phonon interactions can improve the efficiency of magnetic refrigerators, which are not yet practical as household appliances. The "magnetocaloric" alloy La1Fe11.5Si1.5, with chemical substitutions for La and Fe, holds promise for practical refrigerators. Perhaps spin-phonon interactions in a variant of La1Fe11.5Si1.5 can couple the large heat capacity of atom vibrations to the change in magnetism with temperature. This research is an experimental study of how magnetism changes the thermal expansion of metals such as Fe-Pd, La1Fe11.5Si1.5, and perhaps EuO. Labs at Caltech are used to measure heat capacity, magnetization, and thermal expansion at temperatures from 2-400 K in applied magnetic fields. Three different types of X-ray scattering measurements at the Advanced Photon Source in Argonne, IL, provide a detailed understanding of vibrations and spins. The work is part of a Ph.D. thesis at Caltech. The graduate student and the principal investigator are mentoring a summer undergraduate research fellow, and mentoring high school students in a new summer program at Caltech to show them first-hand how scientific research is done. TECHNICAL ABSTRACT Thermal expansion and magnetocaloric properties of ferromagnetic metals are studied with measurements of heat capacity and magnetization at temperatures from 2-400 K and magnetic fields up to 9 T. Materials of interest include Fe-Pd, chemical variants of La1Fe11.5Si1.5, and perhaps Tb-Dy and EuO. Measurements with nuclear resonant scattering of synchrotron radiation provide entropies from both atom vibrations and magnetism. The data are acquired with the samples under pressure in diamond anvil cells. Thermodynamic Maxwell relations convert the pressure dependences of vibrational and magnetic entropies to thermal expansion. For the overall thermal expansion, the vibrations and spins can work for or against each other. Less understood are interactions between spins and atomic vibrations. Some spin-phonon interactions in iron alloys are large enough to have measurable effects on thermophysical properties. Assessments of spin-phonon interactions use nuclear resonant inelastic X-ray scattering measurements of phonon spectra as pressure drives the material through its Curie transition. The entropy of the Curie transition is obtained from heat capacity measurements and is used to determine magnetocaloric properties of interest for magnetic refrigeration. There is evidence that interactions between spins and phonons can pull some of the large phonon entropy into the magnetic transition, which could either enhance or diminish magnetocaloric efficiency. The work is research for a Ph.D. student at Caltech. A summer undergraduate research fellow is also mentored and supported. Through the ongoing Caltech Summer Research Connection, a new program, "Thinking Like a Scientist," is being developed, where three high school students embedded in our research group learn how to formulate a hypothesis in applied physics or materials science and write a proposal to test it. In six weeks, they learn how materials scientists plan and do their work and develop confidence that they can do it, too. 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 · 2024-11

NON-TECHNICAL SUMMARY — Until 1982, scientists thought they knew the rules governing all possible ways to arrange atoms in a solid structure. Then quasicrystalline solids (or quasicrystals) were discovered. This unique group of metallic alloys have ordered atomic structures, revealed by their interactions with X-rays or electrons, but they lack the essential property of crystals, a repeating unit cell. For another 30 years, the only known way to make quasicrystals was by careful metallurgical processing. Then two natural quasicrystalline minerals were discovered in fragments of a heavily shocked meteorite, motivating an experimental study that demonstrated synthesis of quasicrystals from crystalline starting materials in a transient high-pressure and high-temperature event. This synthesis pathway has proven to be fruitful for discovering new compositions of quasicrystals with numerous potential applications, ranging from non-stick coatings to switchable magnets. However, recovery of quasicrystals after a shock event does not show us how and when during the event the quasicrystals nucleate and grow. This question was addressed by a novel series of recent experiments that used a laser-driven shock wave combined with a short, brilliant X-ray pulse to capture diffraction patterns in real time during quasicrystal formation. In some of those experiments, the shocked material launched from the back of the targets was recovered. This work is dedicated to the careful, microscopic study of this recovered material. Each sample is being studied to determine what phases are present; whether they are crystalline, quasicrystalline, or amorphous; and what their compositions are. The results are cross-referenced against the diffraction results to pin down when and how the corresponding quasicrystal diffraction patterns appeared. The result will be a basic understanding of why this method of making quasicrystals works, in the lab and in nature, and a guide to further discoveries of novel quasicrystal-forming alloys with new properties to test and explore. TECHNICAL SUMMARY —The discovery of quasicrystal recovery from natural impacts, experimental shocks, electrical discharges, and nuclear explosions creates a new pathway to discovery and synthesis of interesting novel quasicrystals but also creates numerous basic questions. A complete understanding of the sequence of events in these experiments—and the relative importance of thermodynamic stability and of kinetic constraints—depends on combining transient diffraction data with detailed examination of the recovered products, which is the goal of this work. The main body of the work relies on electron microscopy techniques for phase identification and characterization. Each recovered sample is isolated from the soft-catch plate, mounted, and examined optically and with secondary and back-scattered electrons. Polished surfaces are probed using electron backscatter diffraction to identify domains (as small as 1 micrometer) that yield high-contrast diffraction patterns but cannot be indexed to any unit cell. Often, such spots show obvious five-fold symmetry axes diagnostic of the icosahedral (quasicrystal) phase. The most promising grains are characterized for composition using both energy-dispersive and wavelength-dispersive X-ray spectroscopy. Identified quasicrystal domains will be thinned to electron transparency with a focused ion beam and then studied by transmission electron microscopy to determine their defect density, six-dimensional unit cell parameters, and other characteristics. All this information will be considered in the context of the transient X-ray results from their synthesis experiments. This work is distinctly interdisciplinary in nature and is helping to forge new pathways for discovery at the boundaries between condensed matter physics, materials science, crystallography, and geochemistry. The quasicrystal story is suitable for engaging public outreach and this work will make for excellent multimedia products describing the work and its importance in basic and applied science. The studied and prepared specimens will be uploaded to a discoverable sample and data archive for sharing with other researchers. Participants in the work will range from undergraduate researchers to postdoctoral fellows, leveraging this research into opportunities to engage and attract the next generation of talent. 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 · 2024-11

This project will study the asymptotic behaviors of several stochastic models in probability theory, in terms of long-time dynamics and static spatial limits. These models find wide applications in various disciplines, including condensed matter physics, material science, computer science, and biology, in the study of objects such as quantum particles in disordered media, the growth of bacterial colonies, traffic flow, and the kinetic theory of gases. A focus is to understand universality, the phenomenon where microscopically different probabilistic models produce the same limiting behavior. This project also contains educational components, including curriculum development and supporting K-12 extracurricular math programs. The specific models to be investigated fall into three categories. The first is the Anderson model described by the lattice Schrödinger equation with i.i.d. random potentials. The main objective is to mathematically establish the localization phenomenon, where wave packets do not spread. The principal investigator (PI) plans to carry out comprehensive studies of this model under reduced regularity assumptions. The second theme of this project is the Kardar-Parisi-Zhang (KPZ) universality, which describes the scaling limit of various random growth processes. In the past quarter-century, enormous progress has been made on those with exact-solvable structures. The PI will use geometric and probabilistic methods to study the asymptotics of several such exactly-solvable models, including local environment limits and scaling limits under large deviation, and a limiting random geometry termed the directed landscape. The ultimate goal is to extend KPZ universality beyond exact-solvability. The third topic concerns Gibbs samplers, which are Monte Carlo Markov Chain (MCMC) algorithms used to sample high-dimensional distributions. The focus is on the continuous state space setting, where tools to analyze time evolution are relatively limited. A particular instance is Kac's walk from kinetic theory, whose order of mixing time was only determined in recent years. The PI plans to develop a general framework to understand the mechanism behind the evolution of these Gibbs samplers, and prove predicted cutoffs for them. 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 is to install, commission and operate a fully cryogenic, 26cm aperture near-infrared telescope at Concordia station in the Antarctic. This instrument, called the Cryoscope Pathfinder, is actually a quarter-scale prototype for a cutting edge wide-field 1-meter class telescope that will be designed for multi-messenger astrophysics. Cryoscope Pathfinder will demonstrate this new technology for the first time by conducting a survey to detect transient and time varying events in the near-infrared from Antarctica, a site with ideal conditions to showcase the improvements over previous telescopes. Cryoscope Pathfinder is a technology demonstrator for a very wide field infrared survey telescope that will deliver the sensitivity and field of view (FOV) required to localize infrared transients such as the neutron star – black hole mergers detected by LIGO.  The telescope is optimized for operation in the K_dark spectral passband which falls between the last atmospheric airglow lines at 2.35 microns and the onset of water absorption at 2.55 microns. To take advantage of this atmospheric window, a new approach was required since established techniques cannot reduce thermal emission from the telescope below that of the darker sky while delivering the tens of square degrees FOV required for a rapid survey rate. Cryoscope Pathfinder is thus specifically designed to take advantage of the K_dark band which is unique to the cold sky over Antarctica, and it can only reach its full potential on the high plateau of Dome C due to the lower temperatures and better atmospheric stability (seeing) than are found even at the South Pole.  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 magnitude of future atmospheric surface warming driven by greenhouse gas forcing depends on (i) the rate of emissions, (ii) the strength of atmospheric radiative feedbacks, and (iii) the rate of global ocean heat uptake. A central aim of climate research has been to reduce uncertainty in radiative feedback processes, given their dominant role in setting Earth’s equilibrated warming response to greenhouse gas emissions — warming reached many centuries from now. In contrast, far less focus has been placed on understanding the ocean heat uptake processes that govern the rate of warming – which is arguably of greater relevance to society and climate policy. The ocean-heat-uptake driven influence on surface warming can be quantified by the Ocean Heat Uptake Efficiency (OHUE), defined as the global mean rate of ocean heat uptake divided by the global mean surface temperature anomaly. OHUE has widely been interpreted as representing how efficiently ocean dynamics move heat from the surface ocean to depth, with its time dependence being the primary control on the pace of climate warming. However, there is a wide spread in the magnitude and time dependence of OHUE across global circulation models (GCMs), resulting in divergent predictions of the rate at which long-term warming is reached. This spread reflects the fact that the dynamical ocean processes underlying OHUE and its time dependence are not well understood. This project will employ a hierarchy of numerical tools to (i) characterize the time dependence and spread in OHUE across GCMs and over a range of timescales (ii) identify the underlying mechanisms governing OHUE across different timescales and dynamical regimes, and (iii) identify new observational constraints, which can be used to reduce uncertainty in OHUE across various time-horizons. The scientific outcomes of the project will have far-reaching community and societal relevance. In the near term, the project will generate practical metrics that, when leveraged with oceanic observations, will reduce uncertainty in the future global surface warming rate across different timescales. Further, the collaborators involved are chosen to solidify lasting connections between synergistic research efforts at Caltech, University of Washington, and New York University. Thus, in a longer-term sense, this project will ensure ongoing collaborative efforts and scientific output. The project would also support an early career scientist as a Senior Research Associate. In doing so, it would facilitate her ongoing graduate student mentorship and enable her to advise an undergraduate student under the Caltech Summer Undergraduate Research Fellowships (SURF) Program. The project’s SURF student component is structured to impart valuable insight into ocean dynamical theory and climate sensitivity, as well as scientific research skills. More broadly, the idealized modeling components of this project would provide effective teaching tools to be incorporated into coursework at Caltech, amplifying the impact of the project’s scientific goals. This project aims to rectify a major gap in climate research by targeting OHUE, the primary source of uncertainty in future warming rates. It will lead to an improved understanding of oceanic processes governing the rates of ocean heat uptake and the atmospheric surface warming across a range of timescales. Through the targeted use of a novel numerical model hierarchy, this study will advance the process-level understanding of OHUE and yield a deeper theoretical grasp on the role of oceans in climate. A central hypothesis is that the time dependence of OHUE is set not only by the efficiency of processes moving heat downward away from the surface ocean, but also by the processes that determine how long that heat is sequestered before re-emerging at the surface. This work will shed new light on future climate evolution, namely by identifying the drivers and the timescale of a key multi-centennial transition in OHUE dynamics— from a “downward” heat transport regime” to an “upward” regime. The work could thus provide a physical theory for why the rate of climate equilibration and surface warming under greenhouse-gas forcing is spread so widely across GCMs, and in doing so, improve our understanding of one of the major uncertainties in climate projection. 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

Many geologic basins around the world are heavily faulted, with the number of faults in the hundreds. Predicting the response of such basins to earthquakes or other subsurface events requires understanding the mechanical response of the fault network to external forces like the flow of underground water. Dynamics of individual faults in the network can be different when compared with the dynamics of the overall network because the faults interact with each other via stress transfer mechanisms. This interactive behavior among faults affects the earthquake distribution and ground deformation pattern for the basin. Most existing geological models struggle to capture these dynamics because they lack the ability to account for such differences among faults within the network. This project builds an AI Model using satellite data, subsurface imagery, and other geological information to better understand fault dynamics. This work will enable assessment of regional earthquake and hazard probabilities in tectonically active regions. The model will further provide insight into sustainable and cleaner energy processes of the future. Joint workshops on AI in computational mechanics and seismology will be held to train, upskill, recruit, and reward a diverse body of undergraduate and graduate students. This project builds a multiphysics fault network model to discover reduced-order governing equations for the evolution of stress in complex fault systems. The study region is the Southern Permian Basin in the Netherlands. It uses a novel Computational Graph Discovery and Completion algorithm with Gaussian Process kernels to discover the reduced-order governing equations describing the evolution of stress and stability in the network. These network governing equations are hypothesized to provide orders of magnitude gain in computational speed relative to the current direct numerical simulation algorithms used in the field and will additionally provide insights into multiphysics effects of fluid injection/extraction on stress transfer mechanisms. This model will create new opportunities in subsurface imaging by assimilating flow, petrophysical, seismic, and geodetic data to discover hidden fault networks capable of hosting earthquakes. This award by the Division of Research, Innovation, Synergies, and Education within the Directorate for Geosciences is jointly supported by the Division of Mathematical Sciences within the Directorate for Mathematical and Physical Sciences. 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

PROJECT SUMMARY Overview. This U01 proposal is dedicated to advancing the Human Virome Project (HVP) by addressing several key objectives outlined in RFA-RM-23-018 NOFO. The project's focus is on the development and validation of innovative technologies that enhance rigor and reproducibility of virome discovery and characterization, particularly in human tissue samples. By addressing challenges such as low-biomass sample analysis, host and environmental DNA contamination, and the need for more effective viral quantification and enrichment techniques, this proposal aims to significantly advance the field of virome research. Goals and Objectives. The project is structured around three specific aims: Development of Viral-MEM: An innovative viral enrichment technology that operates independently of viral-like particles (VLP). Viral-MEM is designed to effectively process high-host load tissue samples by removing host nucleic acids while preserving and separating viruses and other microbes. This technology, building on our validated microbial enrichment method, is crucial for deep characterization of viral and bacterial fractions, improving limits of detection in sequencing, and aiding in the identification of novel viruses. Development of Viral StochQuant: A novel experimental and computational approach designed to increase the rigor and reproducibility of viral sequencing. This method uniquely combines sequencing measurements with absolute anchoring measurements to accurately track the absolute numbers of molecules throughout the sequencing process. It addresses the challenges of low target abundance and high background signal, and uses anchoring measurements and stochastic simulations for deriving limits of detection, measurement noise, differential abundance analyses, and contamination detection. Validation of Developed Technologies: Validation will address both biological and technical variabilities and be conducted in three distinct and challenging human tissue sample sets—daily sampled vaginal swabs, saliva samples paired with small-intestine biopsies, and paired biopsies from four locations in the human lower gastrointestinal (GI) tract. This approach will facilitate study of intricate phage-bacterial dynamics, connections between different human viromes, and the quantitative biogeography of the human virome along the GI tract. Impact. The successful implementation of this proposal will dramatically enhance the accuracy, cost- effectiveness, and scalability of virome analyses in human tissues. The technologies developed will enable a more comprehensive integration of virome data with broader human microbiome research and will offer new insights into virome dynamics and interactions. Importantly, these innovations will diversify the HVP's research capabilities, provide access to new sample types, and improve data quality, particularly for low-biomass samples. Overall, this project is designed to provide tools that significantly deepen our understanding of the human virome and its implications in health and disease.