University Of Southern California

NIH Research Projects · FY 2026 · 2025-04

Abstract Pneumonia is a common cause of mortality, particularly in patients with lung cancer or lung diseases. Alveolar macrophages (AMs), the primary phagocytes that serve as the major sentinels in the lung, have been believed to be the main culprits of the fatal pathogenesis. However, it remains largely unknown how these key innate immune cells are transformed to promote lung cancer or lung diseases and to increase vulnerability to infection. In fact, it is still largely unknown how AMs are armed with the strong ability to clear pathogens and mutated cells while simultaneously maintaining immune tolerance within the lung under normal conditions. To address those scientifically and clinically important issues, we have recently identified a unique characteristic of AMs in the inherent expression of the immune checkpoint PD-L1 and a previously unknown role of PD-L1, via cis- interaction with CD80, in rendering AMs highly phagocytic. PD-L1 also arms AMs with a super T-cell suppressive ability, indicating an innovative mechanism by which AMs provide optimal protective immunity and tolerance within the lung. Furthermore, we have identified the PDZ-LIM domain-containing protein PDLIM2, a tumor suppressor recently uncovered by us, as a new determinant of AMs required for CD80 induction and AM phagocytosis. By promoting degradation of the master pro-inflammatory transcription factors NF-B RelA and STAT3 in the nucleus, PDLIM2 is also required to restrict monocyte pulmonary recruitment and differentiation into AMs and to inhibit AM inflammatory activation, thereby limiting inflammation. Amazingly, selective deletion of PDLIM2 in AMs and myeloid cells alone is sufficient to induce lung cancer in mice and makes animals more vulnerable to deaths by the bacterial endotoxin LPS. On the other hand, PDLIM2 is repressed in the AMs of patients with lung cancer, chronic obstructive pulmonary disease (COPD), and interstitial lung diseases (ILDs), and this repression is associated with disease severity and poor patient survival. Of note, PDLIM2 repression in AMs is induced both in vivo and ex vivo by smoking, the most predominant cause of lung cancer and diseases and a prominent risk factor for pneumonia and pneumonia death. Based on these original new discoveries, we hypothesize that PDLIM2 repression in AMs not only promotes lung cancer and lung diseases but also increases vulnerability to lung infection. To test the hypothesis, we will determine the physiological and pathophysiological significance and the detailed mechanisms of the novel PDLIM2/CD80/ PD- L1 signaling pathway in AM phagocytosis, immune response, and bacterial pneumonia. These studies will improve our understanding of lung innate immunity, inflammation, infection, and pathogenesis, and may reveal new therapeutic targets and approaches for better lung disease treatment.

NIH Research Projects · FY 2026 · 2025-04

It has been estimated that more than 50% of prostate cancer (PCa) is inherited, with studies suggesting that both rare, moderate- to high-penetrant pathogenic variants (PVs) as well as more common variants of lower penetrance are important in explaining inherited susceptibility. Evidence to support this includes men with familial or hereditary PCa are at an increased risk for being diagnosed with PCa, and notably more likely to be diagnosed with aggressive clinical features. Rare mutations in DNA repair genes have been implicated in risk for multiple cancers including PCa, and screening for these mutations can determine eligibility for systemic therapies in the metastatic setting. Common genetic variants have also been demonstrated to play a critical role in PCa susceptibility, with polygenic risk scores (PRS) used to identify men with substantially elevated lifetime risks of overall PCa and aggressive disease. Unfortunately, studies investigating the genetic basis underlying familial aggregation of PCa in men of African ancestry have lagged behind those in men of European descent. While the PRS has shown consistent risk estimation across populations, we and others have found that the prevalence and spectrum of rare PVs in the African American (AA) population may be different than in populations of European ancestry. Integrating gene panel testing and PRS has the potential to provide men with PCa with more accurate information about genetically-informed treatment, risk for second cancers, and for unaffected relatives within the family, future cancer risk. The proposed investigation aims to define the genetic factors underlying familial PCa in AA men and to develop risk prediction models for AA men that incorporate the independent and combined effects of PRS, PVs and family history of PCa. To accomplish this, we will leverage existing genetic data for 24,000 unselected AA PCa cases and controls, which includes the RESPOND cohort, a landmark study of over 12,600 AA PCa cases identified through population-based registries from across the United States, including 7,500 with DNA and genetic information [whole-genome sequence (WGS) data], and 45% reporting a first- and/or second-degree FH of PCa. For this study, we will enroll additional eligible first- and second-degree affected and unaffected family members identified through RESPOND probands to study genetic factors that contribute to familial risk of PCa in AA men (Aim 1). Determine the relative contribution of germline variants to familial clustering of PCa and aggressive disease characteristics within unselected cases and controls (Aim 2) and in AA families in RESPOND (Aim 3). Simultaneously, we will develop and test a risk prediction tool for PCa specifically designed for AA men, that incorporates information on the joint impact of rare variants, PRS, and familial risk in AA families (Aim 4). Through this work, we aim to define the prevalence and spectrum of genetic variants in AA men that contribute to familial PCa and develop a PCa risk prediction tool specifically designed for AA men that can be used for counseling AA men about their risk and as a tool for future risk-stratified screening approaches.

NSF Awards · FY 2025 · 2025-04

Gas seeps on the sea floor inject huge amounts of methane into the ocean along the coasts. Most of this is eaten by tiny organisms who rely on oxygen to consume the methane, a process called 'methane oxidation'. Oxygen levels vary naturally throughout the world’s oceans, so it is not known whether the ability of these organisms to consume methane is disrupted in some places. Custom one-of-a-kind instruments to measure methane consumption rates and monitor what organisms are present have been built by the investigators. The instruments will be sent to the bottom of the ocean for weeks and in different locations. The goal is to see how methane oxidation and the types of organisms present adjust to different oxygen concentrations and other environmental conditions. Natural gas seeps along the continental margins inject huge amounts of dissolved methane into overlying waters. This methane is largely oxidized by microbes. Although microbial methanotrophs are largely microaerophilic, it is not known how differences in oxygen concentrations enhance or hinder their ability to respond nor whether methane consumption rates are controlled by deep-sea oxygen concentrations. Recent work has shown that microbial aerobic methane oxidation (MOx) in the deep sea occurs with widely varying rate constants. The project is to explore factors that drive this variation by making in situ measurements of MOx and microbial community dynamics at known seep sites offshore Louisiana, an area with frequent episodic methane releases, and on the Cascadia Margin offshore Oregon where highly variable bottom water dissolved oxygen (DO) will provide vital evidence for how oxygen limitation affects MOx in situ. The in situ measurements are possible due to newly-developed benthic landers that can make MOx rate measurements on timescales of hours to weeks using advanced laser methane and optode DO sensors. An in situ collection and incubation scheme allows collection of microbial time-series, tracking the relative abundance of methanotrophs (through 16S rRNA surveys and metagenomes) and their activity (through metatranscriptomes) to study methanotrophic responses to varying ambient conditions. 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

Hepatitis B virus (HBV) can cause severe liver diseases including cirrhosis and hepatocellular carcinoma (HCC). There are approximately 254 million people in the world that are chronically infected by this virus, resulting in more than 1 million deaths every year. Most chronic HBV carriers acquired the virus early in life from their infected mothers. In contrast to the mother-to-child transmission (a.k.a. vertical transmission), patients who acquired HBV from unrelated individuals (a.k.a. horizontal transmission) usually developed self-limited acute infection. The goal of our research is to understand how HBV and its antigens in the mother affect anti-HBV immunity of her children to promote chronic HBV infection in the latter. HBV has a very narrow host range, which has greatly hampered its research. We have developed a mouse model to study how HBV in the mother affects anti-HBV immunity of her children. By crossing female hemizygous HBV transgenic mice to male naïve mice, we obtained non-transgenic mouse pups. When the HBV genomic DNA was introduced into the liver of these non- transgenic mouse pups by hydrodynamic injection, HBV persistently replicated in these mice for up to 28 weeks. In contrast, HBV was not able to persist in control mice born to non-transgenic dams and was cleared from the mice within 4 weeks after the DNA injection. Our further studies indicated that maternal HBV could educate fetal Kupffer cells (i.e., hepatic macrophages) of the offspring in utero. These Kupffer cells would then undergo M2- like anti-inflammatory polarization to suppress HBV-specific CD8+ T cells after birth, resulting in HBV persistence in the offspring. In contrast, Kupffer cells of the offspring that were not exposed to maternal HBV in utero would undergo the M1-like proinflammatory polarization to promote HBV clearance. During this grant period, we will continue to investigate how maternal HBV and its antigens affect offspring immunity against HBV. Specifically, we will identify maternal HBV factors that promote and support HBV replication in the offspring and their effects on anti-HBV immunity of the offspring. We will also examine the molecular mechanism by which HBV and its antigens use to cross the placental barrier to education fetal immunity. As our preliminary studies suggested that maternal HBV antigens could genetically reprogram fetal Kupffer cells to result in their distinct anti-inflammatory response to HBV after birth, we will also determine the molecular mechanism of this reprogramming. Our proposed studies will provide important information for us to understand how HBV and its antigens in the mother affects anti-HBV immunity of her children to promote HBV replication and persistence after its mother-to-child transmission. This information will be important for the development of novel treatments for chronic HBV patients.

NIH Research Projects · FY 2026 · 2025-04

Here we propose to develop a new tool to treat small cell lung cancer (SCLC) based on an abnormal post- translational modification, isoaspartylation (a type of protein damage involving kinking of the protein backbone) of the ELAVL4 protein. ELAVL4 is expressed on the outside of SCLC tumors. Isoaspartylation is a modification that gives rise to an antibody-based immune response in SCLC patients. In the case of ELAVL4, a naturally- occurring low level antibody response in ~15% of SCLC patients to ELAVL4 is associated with improved response to therapy and significantly improved survival. In addition, rare SCLC patients with spontaneous high- titer anti-ELAVL4 antibody responses show complete regression of this normally highly lethal cancer. However, while the cancer in the latter patients can be completely eradicated, epitope spreading (common with isoaspartylation) leads to the immune response attacking the native protein, causing destruction of healthy neuronal tissues (which express native ELAVL4), and ultimately patient death. The off-target effect in the latter patients is a highly undesirable side effect of an immune response which started against SCLC. However, the efficacy of the immune response in eradicating a highly metastatic cancer shows the power of anti-ELAVL antibodies. Using a genetically-engineered SCLC mouse model that accurately recapitulates human SCLC (including the anti-ELAVL4 response), we recently showed that immunizing SCLC-carrying mice with isoAsp- ELAVL4 significantly improves survival. This indicates that an artificially-induced immune response against ELAVL4 can be therapeutic. However, immunization risks epitope spreading and neuronal toxicity. These can be avoided by instead generating a monoclonal antibody (mAb) specific for isoaspartylated ELAVL4. Such an antibody could be used on its own, could be functionalized, used as part of bi/tri-specific antibodies, or grafted onto T-cells to develop CAR-T therapy. The goal of this project is to generate an isoaspartyl-ELAVL4-specific mouse mAb as a new therapeutic tool for SCLC and to test its therapeutic efficacy in the murine SCLC model. We have 2 specific aims: 1) To generate a mouse monoclonal antibody specifically targeting isoaspartylated ELAVL4 by immunizing with a synthetically-produced isoAsp-ELAVL4 peptide followed by affinity optimization. The binding kinetics and affinity of candidate mAbs for isoAsp-ELAVL4 will be measured to obtain a mAb with optimal binding kinetics (faston, slowoff). 2) To test the therapeutic efficacy of an anti-isoAsp- ELAVL4 monoclonal antibody in the mouse SCLC model. SCLC will be induced in mice with homozygously floxed Tp53 and Rb1 by intratracheal instillation of Adenovirus carrying Cre recombinase, a model we have used extensively. We will produce and purify the optimal anti-isoAsp-ELAVL4 mAb from Aim 1 and test its therapeutic efficacy using survival as an endpoint. If successful, the antibody would be humanized for clinical trials of SCLC patients. Patients with other cancers (e.g. neuroblastoma, breast, ovarian, and prostate cancer) can also exhibit ELAVL4 autoantibodies, hinting at the potential of using this strategy to treat other cancers.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY Blood regeneration must constantly adapt to bleeding, infection, injury, and disease. These processes rely on cell-cell communication to hematopoietic stem cells, HSCs, that are responsible for maintaining the homeostasis of the blood and immune systems. To fulfill this role, HSCs must engage in cell-cell communication with the surrounding cells in the bone marrow. Previous studies have demonstrated that some of these cells, including mesenchymal cells, vascular cells, and osteoblasts, referred to as their niche, play significant roles in regulating and maintaining HSCs via signaling pathways like KIT, CXCL, and VCAM. In these pathways, HSCs play the role of receiver by expressing the receptors for the ligands the niche cells produce. Several studies have suggested that HSCs play active roles in signaling within the bone marrow as well. Not only do they express the receptors for the ligands their niche produces, but they also secrete ligands to their microenvironment. However, individual HSCs do not have even access to these ligands in the dense, semi-fluid, heterogeneous bone marrow environment. This observation, coupled with the fact that gene expression within HSPC populations is heterogeneous, suggest significant signaling heterogeneity in the bone marrow. From my preliminary studies, HSCs exhibit heterogeneous signaling patterns with their niche, immune cells, and other hematopoietic progenitor cells (HPCs), some of which significantly correlate across individual cells. Further, it has been shown that HSPC homing to the bone marrow niche significantly alters with the circadian clock and preliminary data suggests circadian rhythms modulate gene expression and signaling in a lineage-specific manner. Given these preliminary findings, I hypothesize that individual HSPCs are engaged in diverse intercellular signaling pathways in the bone marrow that coordinate with each other and alternate around the circadian clock. The goal of this project is to better understand cell-cell signaling in the bone marrow between HSPCs and their microenvironment and how these signals influence their cell fate decisions and change around the circadian clock in the following three Specific Aims. Aim 1. To use single-cell RNA-sequencing data from HSPCs, their niche, and mature immune cells paired with single-cell spatial data from bone marrow to predict cell-cell signaling pathways. Aim 2. Determine intercellular signaling correlations to construct cell-cell signaling networks. Aim 3. Determine the impact of the circadian clock on HSPC’s intercellular signaling and production of blood and immune cells. In doing so, I will establish a compendium of potential pathways that influence HSPC fate decisions and elucidate the impact of circadian rhythms on HSPC signaling and blood and immune production.

NIH Research Projects · FY 2026 · 2025-04

Abstract Hepatitis delta virus (HDV) is a satellite virus of hepatitis B virus (HBV); thus, infection occurs only in individuals with concurrent HBV infection. Currently, more than 35 million people worldwide are persistently coinfected with HBV-HDV. Coinfection with HDV substantially exacerbates liver inflammation, accelerating the progression to end-stage liver disease (ESLD) within 5-10 years, whereas HBV mono-infection typically requires 40 years to develop ESLD. Currently, no effective therapy is available, presenting a significant public health threat. To mitigate the disease burden, elucidating the mechanisms underlying HDV pathogenesis is imperative. Melanoma Differentiation-Associated Gene 5 (MDA5), a pattern recognition receptor (PRR), is thought to play a central role in recognizing HDV infection. Our genetic, biochemical, and signaling studies reveal that HDV infection of human hepatocytes produces viral RNA species that act as pathogen-associated molecular patterns (PAMPs), resulting in a potent activation of MDA5 signaling. This event promotes a robust and constitutive induction of over 300 antiviral genes, namely interferon-stimulated genes (ISGs). Despite the strong activation of the hepatic IFN system, which is expected to repress the viral lifecycle, our study found that HDV displays significant resistance to the antiviral properties of ISGs. Furthermore, one of the ISGs, adenosine deaminase acting on RNA 1 (ADAR1), is indispensable for the HDV lifecycle as it introduces a site-specific viral genome mutation necessary for producing two viral protein isoforms—small- and large- hepatitis delta antigen—that regulate genome replication and virion assembly, respectively. These findings suggest that MDA5 signaling functions as a proviral, rather than an antiviral, host factor in HDV infection, challenging the existing paradigm. Moreover, our transcriptome analysis and polysome profiling suggest that the constitutive and potent ISGs induction by HDV leads to the activation of programmed cell death through their protein translation inhibition properties. These observations form the basis of our central hypothesis: “HDV exploits the ISGs induction pathway to sustain its viral lifecycle, while simultaneously mediating pathogenesis through the activation of programmed cell death”. Accordingly, this exploratory proposal is designed to elucidate the mechanism and significance of the viral innate immune evasion program as the critical pathophysiology of HDV infection through the following specific aims: Aim 1: Determine the proviral role of MDA5 signaling in HDV infection and Aim 2: Define the mechanism of HDV infection-induced hepatocyte-intrinsic programmed cell death. Both aims are centered around the host response to HDV infection, in particular the robust and persistent induction of ISGs. The successful completion of the proposed studies will provide novel insights that aid knowledge gaps in our understanding of HDV pathogenesis and provide the framework for future investigations with in vivo models as well as clinical specimens, ultimately leading to the development of novel therapeutic strategies.

NSF Awards · FY 2025 · 2025-04

This Faculty Early Career Development (CAREER) award supports fundamental studies to enable scalable manufacturing of high-resolution, liquid metal-based stretchable electronics. Gallium-based liquid metals uniquely combine metallic conductivity and fluidity, making them attractive for applications in wearable biomedical devices, soft robotics, and human-machine interfaces. However, their high surface tension and spontaneous oxide formation pose challenges in patterning liquid metals with high resolution, throughput, and stretchability on a broad range of substrates—a critical obstacle to their wide adoption in high-performance stretchable electronics. This project seeks to address these limitations by developing a novel manufacturing approach that incorporates colloidal self-assembly, surface functionalization, and micro-transfer printing to enable scalable, high-resolution patterning of liquid metals on substrates with high stretchability. The knowledge generated from this work will advance the synthesis, processing, and functionalization of liquid metals for a wide range of applications, including bioelectronics, thermal management, and soft robotics. This CAREER award also includes educational activities aimed at preparing future scientists and engineers in electronics manufacturing to meet the nation’s workforce needs. This project aims to address knowledge gaps in the physical properties of gallium-based liquid metals and realize high-resolution, high-throughput patterning. A new patterning approach will be developed, combining colloidal self-assembly of liquid metal particles with scalable transfer printing. High-resolution nanomechanical characterization of liquid metal particles, coupled with analytical modeling, will elucidate the processing physics. This self-assembly process will be combined with high-speed, roll-to-roll micro-transfer printing to fabricate liquid metal patterns on various substrates. Furthermore, this project will investigate process-structure-property relationships that govern the patterning resolution and the mechanical and electromechanical properties of multiscale liquid metals formed through this approach. By combining advanced micro/nano-fabrication, material characterization, and modeling, this project will advance the knowledge base of multiscale mechanical and electromechanical properties of liquid metals, enabling scalable production of next-generation liquid metal-based stretchable electronics. 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 · 2025-04

SUMMARY DSBs occur in every cell as a result of cell exposure to environmental mutagens, such as ionizing radiation, or during normal cell metabolism, such as DNA replication. Repairing DSBs is particularly challenging in pericentromeric heterochromatin, a poorly characterized domain in which the abundance of repeated sequences can trigger widespread aberrant recombination and genome instability. We have previously identified a specialized and conserved pathway that promotes faithful homologous recombination (HR) repair of heterochromatin, while preventing aberrant recombination. HR starts inside the heterochromatin domain with resection, but it continues only after a striking relocalization of repair sites to the nuclear periphery. Relocalization likely prevents aberrant recombination by isolating DSBs and their repair templates (on the sister chromatid or homologous chromosome) away from similar sequences on other chromosomes, before strand invasion. A key regulator of this pathway is the Smc5/6 complex that halts HR repair inside the heterochromatin domain through SUMOylation, and promotes DSB mobilization in mysterious ways. Nse5/6 is a linchpin regulator of this complex that mediates Smc5/6 targeting to DSBs while inhibiting its ATP-ase and loop extrusion functions. Despite this critical role, Nse5/6 is an elusive component of the Smc5/6 complex. This rapidly evolving heterodimer is poorly conserved at the sequence level, and it has only been identified in yeasts, mammalian cells, and Arabidopsis. Drosophila cells are currently the best model system to study heterochromatin repair dynamics, but the lack of known Nse5/6 subunits limits our understanding of Smc5/6 regulation in this context. With the overarching goal of illuminating the mechanisms of heterochromatin repair, the objective of this proposal is the identification and characterization of Drosophila Nse5/6, and its functions in heterochromatin repair. We identified strong candidates to perform Nse5/6 functions in Drosophila through a mass spectrometry screening for Smc5/6 interactions and molecular modeling. We will combine structural determination at the atomic level with targeted mutagenesis and assays in vitro and in vivo to identify this missing link in genome stability. Expected positive outcomes of this research include the first identification and characterization of Drosophila Nse5/6 and its functional domains. In addition, we will define new mechanisms specifically targeting Nse5/6 to heterochromatin and repair sites, a novel regulatory function relying on its phosphorylation, and the establishment of its role(s) in heterochromatin repair. These results will have an important positive impact by identifying crucial safeguard mechanisms used by normal cells to protect the genome from environmental threats. These studies are also expected to produce new Drosophila disease models, and to significantly advance our understanding of human diseases resulting from Nse5/6 dysregulation, including cancer, neurodevelopmental disorders, and viral infection.

NSF Awards · FY 2025 · 2025-04

This conference brings together scholars from different areas of language science around the theme of item-specific and abstract knowledge. It is widely acknowledged that users of all languages know both specific facts about their language (e.g., word-specific patterns), and know general rules of their language that they use to adapt to new linguistic situations (e.g., new words they have not heard before). However, current linguistic theories typically prioritize explaining one type of knowledge over the other, and there is not yet a good understanding of how the two different types of knowledge co-exist and relate to one another. This conference brings together researchers with wide-ranging expertise and perspectives for a focused discussion to help advance a scientific understanding of how humans represent and use both types of knowledge. Other benefits to society include educational, networking, and mentorship opportunities for many students who attend the conference. The conference consists of six panels. The panels consider the relationship between item-specific and abstract knowledge in language and cognitive science domains, centered around evidence, modeling, learning, the brain, and language evolution. The conference takes place across two days and is co-located with an established, larger event to maximize conference attendance. In addition to the panel sessions, the workshop includes a poster presentation session and multiple events to promote collaboration and mentorship. A better understanding of the roles of abstraction and item-specificity could lead to improved outcomes in many applied disciplines, including improved diagnosis and treatment of language disorders, and improvements in second language pedagogy. 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 · 2025-03

PROJECT SUMMARY The acquisition of resistance to antibiotics (Abs) in pathogenic bacteria has grown into a worldwide pandemic, with around 3 million cases and roughly 35,000 deaths in 2019, according to the CDC. Bacteria can acquire Ab resistance by the horizontal transfer of specific Ab resistance genes, and by the de novo occurrence of mutations caused by exposure to Abs or to a wide variety of naturally occurring external stressors, e.g., UV radiation, environmental pollutants. Our grant proposal is centered on the acquisition of Ab resistance in bacteria caused by mutations resulting from the transfer of a highly error-prone DNA polymerase, Rum pol, encoded by the integrative conjugative element R391. R391 is found ubiquitously in nature. We have previously shown that the pathogen-encoded Rum pol, in order to be enzymatically active in vitro and active mutagenically in multiple types of recipient bacteria, must be assembled into a mutasomal complex requiring the stable presence of each individual homolog RecA recombinase and ATP, Rum Mut = Rum pol-RecA-ATP. This proposal will test our hypothesis that by generating a broad mutational landscape, Rum pol is responsible for driving the rapid acquisition of Ab resistance in its bacterial recipient cells. We further hypothesize that a single methionine at position 197 in RecA (RecA M197), which is conserved in RecA recipient cell homologs, serves as a “master regulator” for Rum pol mutagenesis and for the acquisition of Ab and multi-Ab resistance. Our recent published data provide strong support for this hypothesis, and new preliminary data strongly reinforce this hypothesis. We will use ICE R391 “donor” and Escherichia coli and Vibrio cholerae recipient bacteria as our model system. There are two in vivo microbiology and two mechanistic based specific aims. Aim 1 investigates the role of Rum pol in rapid acquisition of Ab resistance; Aim 2 maps regions of Ab- and external stressor-induced genomic instability (ssDNA) globally in genomic DNA, maps the location of Rum pol on the genome, and identifies the all of the mutations using NG sequencing; Aim 3 visualizes the assembly Rum pol into Rum Mut at single molecule resolution in real-time using TIRF-FRET microscopy; Aim 4 will obtain high- resolution structures of Activated Rum Mut using Cryo-electron microscopy. An important objective is to identify specific sites in Rum Mut that can serve as targets for the design and discovery of small molecule inhibitors that prevent assembly of Rum pol into mutagenically active Rum Mut or that inhibit the activity of activated Rum Mut.

NSF Awards · FY 2025 · 2025-03

This project explores DNA N6-adenine methylation (6mA) in a unicellular eukaryotic model organism. Though known anecdotally for decades, 6mA's significance in eukaryotic cells has only recently come to light. Advanced DNA sequencing techniques will be used to map 6mA across the genome, providing insights into how this DNA modification is involved in gene regulation. The study focuses on the molecular mechanisms placing 6mA in the appropriate genomic context. Understanding 6mA could reveal new aspects of how genes are turned on and off, shedding light on fundamental processes of life. This research not only advances basic science but also has potential implications for understanding epigenetic changes in health and disease. The project also has strong educational and community outreach components. Data from the study will be shared publicly, supporting other researchers, and the project will involve training students at various levels. This ensures the next generation of scientists is equipped with the knowledge and skills needed to continue advancing this important field. This project will study DNA N6-adenine methylation (6mA) using the unicellular eukaryote Tetrahymena thermophila as a model system. 6mA’s potential as a eukaryotic epigenetic mark has attracted great interest, but its biogenesis and functional implications remain elusive. Tetrahymena is the first eukaryote with 6mA found in its nuclear DNA 50 years ago, and more recently, with a 6mA methyltransferase (MTase) identified and characterized. Using Single Molecule Real-Time, Circular Consensus Sequencing, 6mA on individual Tetrahymena genomic DNA molecules are mapped with high sensitivity and accuracy, and at single-nucleotide resolution. AMT1, a member of the MT-A70 family of MTases, is shown to be crucial for establishing the transcription-associated 6mA distribution pattern in Tetrahymena. Nonetheless, how 6mA is specifically deposited—in the context of transcription, replication, and chromatin—still needs to be elucidated. The PIs will dissect transcription-associated and replication-coupled targeting mechanisms for 6mA deposition. The PIs will also elucidate the biochemical and structural basis for AMT1-dependent, semiconservative, and chromatin-guided transmission of 6mA. This work will provide deep insight into 6mA biology in eukaryotes. 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

The objective of this workshop is to provide a forum for leading construction engineering scholars and professionals to identify the grand challenges in the Architectural Engineering and Construction (AEC) industry. While the construction industry has very low investment in research it is undergoing a significant transformation driven by sustainability imperatives, environmental stressors, and evolving societal needs. With the rise of robotics, artificial intelligence, digital twin technologies, and novel construction materials and manufacturing processes, the industry faces immense challenges and opportunities to catalyze and accelerate innovation. The workshop seeks to deliver the following specific impacts to the research community: (1) provide insights into the current grand challenges and emerging trends in construction engineering research, (2) enhance understanding of the emerging research needs for different areas of expertise within and outside the construction engineering research community, (3) guide the construction engineering research community in aligning their research focus with current needs for the profession and for the society, and (4) provide a research roadmap to define future research priorities both for researchers and for funding agencies to guide construction engineering research. The outcome is broadly disseminated through workshop reports, research roadmaps, and journal publications. 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

NONTECHNICAL SUMMARY This award supports research, education, and outreach activities focused on understanding materials properties driven by the coupling between electrons and the vibrations of atom lattices in solids. This electron-lattice vibration interaction is fundamental to many phenomena, such as electric heating in transistors, light absorption and energy conversion in solar cells, and superconductivity where electric current is conducted with zero loss. The theoretical understanding of these phenomena can be simplified by considering electrons as independent of each other and considering their coupling to the lattice vibrations individually. However, in many topical materials of technological significance, electrons interact strongly among themselves while also collectively coupled to the lattice vibrations. Such strong interaction and coupling leads to exotic quantum phenomena, but it also presents challenges in achieving a clear understanding of the behaviors of such materials. This project addresses these challenges by developing and applying advanced quantum-mechanical computational approaches and large-scale simulation techniques. The goal of this research is to reveal the actual role of electron-lattice vibration coupling in interacting-electron materials systems and to explain intricate phenomena observed in novel superconductors and semiconductors. This project supports the education of a graduate student. Additionally, the project integrates research, community building, education, and outreach activities, by targeting a wide range of researchers, from high-school students to undergraduate students, to graduate students, and postdoctoral researchers. The PI will provide summer internship positions for high-school and undergraduate students and design appropriate research training projects. This project will also support various tutorial workshops to promote advanced computational methods for the young generations and foster collaborations in the scientific community. TECHNICAL SUMMARY This award supports research, education, and outreach activities focused on studying the interaction between phonons and many-body correlated electrons, and the role of electron-phonon coupling in driving exotic phases in and out of equilibrium. The understanding remains elusive largely due to the lack of appropriate ab initio methodologies that treat electron-electron and electron-phonon interactions at the many-body level simultaneously. This project will use newly developed many-body approaches, namely GW perturbation theory and time-dependent adiabatic GW with phonons (where G represents the single-particle Green function and W is the screened Coulomb interaction), to (i) address the role of phonons in unconventional and novel superconductors, and (ii) investigate many-body self-energy effects and nonequilibrium dynamics in phonon-assisted optical phenomena in semiconductors. This project will push forward the ab initio electron-phonon coupling computation into the many-electron level and the nonequilibrium regime, vastly expanding the application scope of many-body perturbation theory to phonon-relevant phenomena. This project integrates research, community building, education, and outreach activities to expose a broad range of generations of students and researchers to various computational and theoretical techniques and scientific advancements. This project will promote novel electron-phonon coupling computational approaches through pilot workshops and foster coherent collaborations among software developers and users. The PI will provide summer internship positions for high-school and undergraduate students via designed outreach and education activities to introduce frontier materials and physics research progress, and to prepare young generations to pursue future careers in science and engineering. 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

NON-TECHNICAL SUMMARY Additive manufacturing, also called 3D printing, is a new paradigm to produce net-shaped components layer by layer for a broad range of technological applications in automotive, aerospace, biomedical and other industries. In addition to vast design freedom, the rapid laser melting during additive manufacturing can produce highly refined structures at the nanoscale in metals for achieving high strength. However, high-strength nanostructured metals often suffer from limited ductility, which is an ability to be stretched without breaking. This strength-ductility tradeoff has been a long-standing challenge in materials science and the quest for materials that can simultaneously enhance strength and ductility has been a long-sought-after goal. High-entropy alloys (HEAs) are a new class of materials that contain high concentrations of five or more different elements in near equal atomic proportions, in contrast to traditional alloys that are primarily based on one major element with some minor alloying elements added. This Faculty Early Career Development (CAREER) award supports fundamental investigations into additive manufacturing of HEAs towards strength-ductility synergy beyond current benchmarks. This project is helping to understand the microstructural origin and deformation mechanism that govern the mechanical properties of 3D-printed HEAs by integrating microstructural characterization, mechanical testing, and computational modeling. The knowledge being established in this project will guide the development of strong yet tough metal alloys for various applications such as advanced energy systems, transportation, and defense. This CAREER award also includes a significant educational component that engages students in research across high school, undergraduate and graduate levels. Through broadening participation of underrepresented groups, this project is diversifying the next generation of researchers and STEM leaders in materials science and advanced manufacturing. TECHNICAL SUMMARY 3D-printed metal alloys usually involve highly localized melting processes, strong temperature gradients, and fast cooling rates. These extreme printing conditions result in far-from-equilibrium states that enable microstructural refinement to the nanoscale for achieving high strength. However, high-strength nanostructured metal alloys often suffer from limited ductility, known as the strength-ductility tradeoff. Through harnessing the extreme printing conditions of laser additive manufacturing and favorable compositional effect of HEAs, a unique type of hierarchical microstructure in the form of dual-phase nanolamellae embedded in microscale eutectic colonies is achieved in 3D-printed eutectic HEAs. This process gives rise to an exceptional combination of strength and ductility. This CAREER award is investigating the fundamental processing-structure-property relationship in these strong yet ductile nanolamellar EHEAs produced by additive manufacturing. The scientific objectives in this study are to: 1) Understand how laser printing protocols affect the solidification microstructure and mechanical properties of 3D-printed eutectic HEAs. Process-sensitive thermal modeling will be developed to unveil the physical link between the complex printing parameters and the solidification microstructure and resulting mechanical properties. 2) Unravel the deformation mechanism and micromechanical response of 3D-printed eutectic HEAs by in situ neutron diffraction and transmission electron microscopy. 3) Elucidate the phase transformation pathways in 3D-printed eutectic HEAs upon post-printing heat treatment. A fundamental investigation of the phase transformation pathways and kinetics during annealing of the far-from-equilibrium 3D-printed HEAs are being performed to expand the palette for materials design. The mechanistic insights and design motifs being provided by this CAREER project have broad implications for the development of hierarchical, multi-phase, nanostructured alloys with excellent mechanical properties. This award also encompasses an educational and outreach plan to advance research training and education of next-generation students and underrepresented groups. New outreach initiatives such as 3D printing workshops and a summer-enrichment program will be developed to inspire women and underrepresented minorities and increase the diversity of our future workforce in materials science and advanced 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 2026 · 2025-03

SUMMARY Advances in human genomics have dramatically accelerated our understanding of the genetics of complex brain disorders, including autism spectrum disorders (ASD), schizophrenia (SCZ), and intellectual disability (ID). De novo mutations in SYNGAP1 have been reported in ASD, SCZ, and ID, indicating a role for SYNGAP1 in complex brain disorders. These mutations occur throughout the SYNGAP1 gene, which encodes multiple isoforms, and likely affect different SYNGAP1 functions. Most studies of SYNGAP1 have been performed in rodent models within the context of mature synapses and its role at early stages of brain development is largely unknown, especially in humans. Human brain organoids from pluripotent stem cells (PSCs) are emerging as a tractable model to reveal genotype-phenotype correlations in a human cellular context. By leveraging cultures of cortical organoids, we found for the first time the protein expression of SYNGAP1 in human radial glia progenitors (hRGP). Mechanistically, we found that the SYNGAP1’s RASGAP domain is essential for cytoskeletal remodeling of subcellular and intercellular components of hRGP. In addition, we discovered that SYNGAP1 regulates the division mode of hRGP with haploinsufficient organoids exhibiting accelerated cortical neurogenesis. We similarly observed an increased ratio of neurons to radial glial progenitors in an embryonic mouse model of Syngap1 mutation, suggesting that Syngap1 controls the timing of cortical neurogenesis in vitro, in vivo, and across species. Furthermore, we identified SYNGAP1 protein interactors with enriched neurodevelopmental (NDD) risk factors in hRGP. These findings lead to our proposal to determine i) the downstream effectors of Syngap1 in hRGP; ii) the function of the SYNGAP1’s PDZ-ligand domain in controlling cytoskeleton remodeling in hRGP; iii) the impact of SYNGAP1 mutations on the trajectory of distinct human cortical cell types; and iv) whether disruptions of members of the SYNGAP1 Protein interaction network (PIN) can converge on dysregulation of human cortical neurogenesis. This work will be essential for reframing our understanding of the impairments in neural circuit function observed in SYNGAP1 patients by connecting it not only with the well-known alteration in synaptic transmission, but also with early developmental defects. It will also aid the stratification of SYNGAP1 mutations according to their effects on the functionality of the SYNGAP1 PDZ-ligand and the RASGAP domain at early stages of human brain development. Finally, by identifying the SYNGAP1 PIN in early brain development, we expect to discover novel signaling hubs associated with NDD that converge on the dysregulation of human cortical neurogenesis which will inform selection and screening of therapeutic targets.

NSF Awards · FY 2025 · 2025-03

This project attempts to find the barrier between tractability and intractability for computational problems of broad interest and central importance. That is, the investigator will try to prove that certain problems cannot be quickly solved by computers. The project will also investigate if certain known algorithms are the best possible ones for these problems. The algorithms considered in this project have been studied extensively, but a complete understanding remains elusive. A central part of the project is mathematically investigating if the plurality voting method is the "democratic" election method that best protects against random corruption or miscounting of votes. Besides suggesting which voting methods are mathematically the best ones to use, the project aims to advance the understanding of what computers can and cannot do in a reasonable amount of time. The final part of the project addresses the method used to train large language models and other artificial intelligence (AI) tools and how well this method works. This training method is known to be deficient in certain ways, and the project will look for new deficiencies in this method. Understanding these deficiencies could lead to better performance of AI tools such as large language models. The project will also train graduate students and include outreach activities to the public for greater understanding of different electoral methods such as ranked choice voting. This project will attempt to prove the following results in complexity theory. (1) The Plurality is Stablest Conjecture (i.e., if votes have been corrupted or miscounted, the best way to determine the winner of an election is to take the plurality.) (2) Sharp hardness of approximation for the MAX-m-CUT problem, assuming the Unique Games Conjecture, which is a central problem in complexity theory of similar importance to the P versus NP problem. (3) Sharp hardness of approximation for the product state Quantum MAX-CUT problem, assuming the Unique Games Conjecture. (4) A weak version of the Unique Games Conjecture over the field of two elements. (5) Improved nonconvergence of the Adam optimization method for online function minimization, for a larger range of parameters. The projects (1) through (4) are closely related, since (1) implies (2), and proving (3) involves a variant of (1). Also, the methods to be explored for (4) are closely related to those used for (1), (2) and (3). 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

NONTECHNICAL SUMMARY Additive manufacturing, also called 3D printing, is a disruptive technology for the manufacture of engineering components in automotive, aerospace, defense, biomedical and other industries. The high-temperature laser beam used for additive manufacturing of metal alloys usually produces highly heterogeneous microstructures that result in large inhomogeneous residual stresses in 3D-printed materials. Residual stresses are generally detrimental to the performance of a material or the life of a component, thus limiting the wide adoption of additive manufacturing in engineering applications. While the macroscale residual stresses have been widely studied in the field of metal 3D printing, the origin and control of the microscale residual stresses remain largely unexplored. This collaborative research aims to understand and control the microscale residual stresses in additively manufactured stainless steel. Due to its excellent combination of mechanical properties, corrosion, and oxidation resistance, stainless steel is a workhorse material used in a wide range of applications such as cars, ships, airplanes, nuclear power plants, medical implants, etc. The research will investigate the effects of 3D-printed microstructures on the resultant microscale residual stresses in stainless steel by integrating microstructural characterization, mechanical testing, and computational modeling. Mechanistic insights gained will be applied to guide additive manufacturing, so as to mitigate the microscale residual stresses in 3D-printed stainless steel. Results from this research will lay a solid foundation for future development of additively manufactured metallic materials with tailored microstructures and outstanding mechanical performance. The project will promote teaching, training, and learning through multi-discipline approaches, broaden the participation of underrepresented groups, and enrich curriculum development efforts, particularly in the interdisciplinary areas of materials science and advanced manufacturing. TECHNICAL SUMMARY Additive manufacturing of metal alloys via laser powder bed fusion and laser engineered net shaping technologies features highly localized melting processes, fast cooling rates, and strong temperature gradients. These extreme laser-printing conditions result in highly nonequilibrium microstructures that lead to severely inhomogeneous residual stresses in additively manufactured materials. The research aims to elucidate the fundamental relationships between the additive manufacturing methods, heterogeneous microstructures and microscale residual stresses in 3D-printed stainless steel. The project consists of two major thrusts. Thrust I involves 3D printing, microstructural characterization, mechanical testing and in situ synchrotron x-ray measurements of residual stresses in stainless steel for a large range of printing schemes and parameters, and accordingly a variety of printed microstructures. Thrust II involves the development of microstructure-sensitive crystal plasticity finite element models that account for the heterogeneous grain structures and sub-grain solidification cell structures. The impact of both intergranular and intragranular residual stresses on the mechanical responses of printed samples will be systematically studied by combining experiments and simulations. Mechanistic insights gained will be applied to guide the optimization of printing schemes and parameters, so as to alleviate the microscale residual stresses in 3D-printed stainless steel. The integrated experimental and modeling approach developed is generally applicable to understand and control the residual stresses in other additively manufactured metal alloys. The project will engage high school students and underrepresented minorities for research. These activities will provide opportunities to inspire their interest in pursuing future career in advanced 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.

NSF Awards · FY 2025 · 2025-02

Cells receive many signals from their environment, including tensions and mechanical forces that are transferred all the way down to their nucleus. Nuclear shape adaptations to those forces are critical for cell fate and function. Yet, the physical and molecular principles underlying those adaptive mechanisms remain largely undefined. By integrating state-of-the-art scientific approaches, this project will generate mechanistic understandings of nuclear mechanics and predictive insights into the organization of force-transmitting complexes in human cells. The work will offer novel rationales to design bio-inspired and force-responsive nanodevices for human health. It will also contribute new perspectives on the normal and defective mechanobiology of the nucleus, advancing our understanding of those critical cellular processes and the diseases that are caused by dysfunction in these systems. A key aspect of the project is the training of early-career scientists, graduate students, undergraduates, and STEM-focused high school students to expose them to a unique research experience at the crossroads of physics and biology. The project will probe and define the physical mechanisms of force transmission at the Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes. These complexes are assemblies of proteins, which exhibit low elastic moduli on their own, but that collectively function as mechanotransducing hubs capable of conveying forces across the membrane of the nucleus, via mechanisms that remain poorly understood. The goals are to identify the molecular tenants governing the formation, maintenance and disassembly of LINC protein clusters as a function of forces applied on the nucleus, to measure forces exerted at these clusters with fluorescent optical force sensors and to formulate physical models that define how LINC complex clustering participates to local changes in the shape of the nuclear membrane and force transmission. The project will integrate theory and experiment. It will be implemented through a multidisciplinary approach involving super-resolution microscopy, single molecule tracking, FRET imaging, cellular nanomanipulation, engineering of novel optical force sensors, their calibration using DNA origami nanoactuators, and theoretical modeling. The project will lead to a better understanding the mechanical properties of the nucleus, its membrane and cell mechanics in general. This collaborative US/France project is supported by the US National Science Foundation and the French Agence Nationale de la Recherche, where NSF funds the US investigator and ANR funds the partners in France. 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

PROJECT ABSTRACT Inherited genetic variation is a key component in the etiology of prostate cancer (PCa). More than 450 common single nucleotide variants (SNVs) for PCa have been identified in large-scale multi-ancestry genome-wide association studies (GWAS) and rare pathogenic SNVs in >30 PCa candidate genes have been implicated across ancestry populations. Although somatic copy number alterations are commonly observed in prostate tumors and predict poor outcomes, studies are limited in evaluating the contribution of germline copy number variations (CNVs) to PCa risk, due to the technical challenges of detecting germline CNVs from genotype and sequencing data. CNVs, the deletion and duplication of DNA segments ≥50 bp, are a prominent class of genetic variation that has critical impacts on human health and disease. Studies with array intensity data have found evidence of both common (≥1%) and rare (<1%) CNVs associated with risk of total and/or aggressive PCa, but these analyses were limited to only large CNVs (>1kb), mostly conducted in populations of European ancestry, and had no or limited focus on aggressive disease. For a thorough investigation of germline CNVs on PCa risk, we propose to combine imputation and sequencing- based approaches to maximize the ascertainment of CNVs across the frequency and size spectrum in the human genome. Leveraging existing GWAS, whole-exome sequencing (WES) and whole-genome sequencing (WGS) data from large-scale studies with disease aggressiveness well-defined, we are well- powered to examine the association of CNVs with risk of total and aggressive PCa and evaluate the joint contribution of CNVs and SNVs on PCa risk. In Aim 1, we will use the 1000 Genomes Project (1KGP) 30X reference panel to impute common CNVs and test their associations in >24,000 men of African ancestry and >113,000 men of European ancestry with GWAS array data. In Aim 2, we will apply GATK-gCNV to detect rare coding CNVs of all sizes in >12,000 men of African ancestry and >41,000 men of European ancestry with WES data. The aggregate association of rare CNVs will be evaluated in gene-based and gene- set analyses. In Aim 3, CNVs of all sizes and frequencies across the genome will be detected using DRAGEN in >10,000 men of African ancestry and >182,000 men of European ancestry with WGS data. Analyses in WGS studies allow for a comprehensive assessment of CNVs genome-wide, independent replication of risk- associated CNVs identified from GWAS or WES studies, and an integrated analysis of polygenic risk score (PRS) and rare CNVs and rare pathogenic SNVs in candidate genes to understand their joint effects on PCa risk and disease aggressiveness across populations. We expect this study to provide the most comprehensive and well-powered investigation of germline CNVs in PCa across populations to date. This study has the potential to advance the field through discoveries of novel risk variants for PCa that could elucidate underlying biological mechanisms and improve risk stratification across diverse populations.

NIH Research Projects · FY 2025 · 2025-01

PROJECT SUMMARY/ABSTRACT Reducing health disparities and inequalities among marginalized populations is a top U.S. public health priority. These disparities exist across a wide range of outcomes, including diabetes, hypertension, obesity, asthma, heart disease, cancer, and preterm birth. Similarly, the burden of exposures to multiple environmental exposures is not evenly distributed among populations. The Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) cohort is a prospective pregnancy cohort of more than 1000 predominantly low- income, Hispanic/Latino mother-child pairs in urban Los Angeles, California. MADRES examines environmental and social determinants of maternal and child health outcomes both during and after pregnancy. A wide range of data are collected including interviewer-administered questionnaires and validated instruments, anthropometric and body composition data, and a broad suite of biospecimens from both mother and child. Environmental exposures were assigned to residential addresses of participants across time (e.g., ambient and traffic-related air pollution) or measured in stored biospecimens (e.g., PFAS, metals, emerging chemicals of concern). The MADRES cohort is a unique resource and one of the largest US environmental health disparities cohorts of predominantly Hispanic mother-child pairs from structurally marginalized communities. The proposed project would capitalize on the significant investment to date and would allow for re-engagement of inactive participants, continued follow-up and maintenance of staff infrastructure, collection of biospecimens for future studies, new opportunities for diversifying the environmental health sciences workforce, and increased capacity for data sharing with the scientific community. We propose the following four specific aims: (1) Maintain, enrich and support the continuation of the MADRES cohort of predominantly low-income Hispanic families; (2) Enhance the existing MADRES biospecimen repository to annually collect blood and urine from mothers and blood, urine and saliva from children to preserve for future studies; (3) Expand data sharing and quality assurance protocols for the MADRES cohort; and (4) Provide opportunities for increasing workforce diversity for early-stage investigators from the undergraduate to postdoctoral levels. We will work across the U24 consortium of cohorts to promote data sharing best practices, development of novel metrics of structural racism and determine common measures for conducting inclusive science.

NIH Research Projects · FY 2025 · 2025-01

ABSTRACT Latinos, one of the largest and fastest growing ethnic groups in the country, face a disproportionate burden of osteoporosis, with over 40% estimated to have low bone mass. The underlying environmental factors contributing to these disparities remain unclear. Per- and polyfluoroalkyl substances (PFAS) are ubiquitous, persistent chemicals and are emerging as potential risk factors for bone toxicity. Animal and autopsy studies have shown that PFAS can accumulate in skeletal tissues, potentially influencing bone metabolism through alterations in osteoclast and osteoblast activities and bone remodeling pathways. However, evidence from human studies is limited, often hindered by small sample sizes, cross-sectional designs, and a lack of focus on the Latino population, which bears a disproportionate burden of metabolic and bone diseases. Additionally, no studies have utilized omics biomarkers to explore the biological mechanisms through which PFAS may affect bone health. To address these critical knowledge gaps, we propose the first prospective study to investigate the effects of PFAS on bone mass, metabolism, and structural quality in a high-risk, overweight/obese Latino population. This study will integrate data from three longitudinal cohorts spanning the life course to understand the impact of PFAS at various stages of bone development and deterioration. Given the challenges of observing a single population over 70 years, this multi-cohort design provides the most effective approach for life course analyses. We will employ robust longitudinal assessments, including bone mineral density (BMD), markers of bone turnover (BTM), and trabecular bone score (TBS), to document the effects of PFAS across different life stages in overweight/obese Latinos. Additionally, we will use proteomics to comprehensively characterize dysregulated pathways affecting bone health, focusing on inflammation and metabolism-regulating proteins. Our specific aims are: 1) Determine the associations between plasma PFAS concentrations (individual PFAS and PFAS mixtures) and measures of bone health (BMD, BTM, and TBS) in Latino adolescents, young adults, and older adults; 2) Investigate the association between plasma PFAS concentrations and plasma protein abundance related to inflammation, bone morphogenic, and maintenance pathways across different age groups; and 3) Develop integrated risk profiles of impaired bone health in Latino populations across the life course. By leveraging three distinct, well-phenotyped cohorts and employing state-of-the-art omics and data science methodologies, this study aims to elucidate the impact of PFAS on bone health throughout the life course. The findings have the potential to inform the development of precision environmental health strategies to identify high-risk individuals and mitigate adverse effects on bone health, thus reducing the overall risk of osteoporosis.

NIH Research Projects · FY 2026 · 2025-01

Project Summary Precise spatiotemporal regulation of lineage-specification genes is critical not only for directing proper development in the early embryo but also for safeguarding cell fate decisions in adult tissues. Histone methyltransferases (HMTs) restrict transcription factor binding by condensing DNA into heterochromatin and thus prevents the formation of developmental disorders. This process can be reversed through the action of pioneer factors, which are capable of binding and decondensing heterochromatin. However, the mechanisms governing where and when a pioneer factor can bind to a given region remains unclear. How different states of heterochromatin may be resistant to pioneer factor binding and activity. Recent work by the Bell lab has identified a unique overlap between the histone 3 lysine 9 (H3K9) dimethyltransferase G9A/GLP and pioneer factors at lineage specification genes bound by the zinc finger protein ZFP462. However, while these overlapping regions are more accessible than those bound solely by G9A/GLP, they are not fully derepressed. In contrast, H3K9 trimethyl (H3K9me3) rich DNA established by SETDB1 remained inaccessible and devoid of pioneer factor binding. Therefore, I propose that unlike TF-resistant heterochromatin established by SETDB1, G9A/GLP creates a poised heterochromatin state which is semi-permeable for pioneer factors and thus facilitates cell fate plasticity during differentiation. To test this, I will compare the heterochromatin states established by G9A/GLP and SETDB1 at unbiased loci using two distinct methods. In aim#1, a tethering reporter strategy pioneered by the Bell lab will recruit G9A/GLP or SETDB1 to the same reporter locus through tethering minimal interaction domains (IDs). Two reporter loci will be utilized for this, one knocked into the endogenous Oct3/4 locus to investigate the established heterochromatin in the context of the OCT4 positive feedback loop and the other in a gene desert on chromosome 7 allowing for modular addition of pioneer factor binding motifs. Repression of the locus will be assessed through expression of the reporter as determined by flow cytometry and ChIP-qPCR probing of the targeted locus for the downstream histone marks and repressive machinery recruited by G9A/GLP and SETDB1. In aim#2, the ability of pioneer factors recruited by endogenous cis- regulatory elements to open heterochromatin during differentiation will be tested by a ZFP462 fusion protein with the C-terminal G9A/GLP-ID swapped with a SETDB1-ID. Through ChIP- and ATAC-sequencing, the establishment of heterochromatin and accessibility of ZFP462 target loci during directed neural stem cell differentiation will be assessed. Additionally, 10X single cell RNA-sequencing during undirected EB differentiation will determine any differences in the capacity of the ZFP462-ID fusion proteins to direct differentiation into the three germ layers. In aim#3, a 6mA footprinting analysis in conjunction with long-read genome sequencing will be performed in the chromosome 7 tethered reporter lines to identify differences in nucleosome arrangement in the different heterochromatin states, both alone and in the presence of pioneer factor binding motifs.

NSF Awards · FY 2025 · 2025-01

Despite its undeniable practical success, machine learning remains poorly understood in many respects. Even some of the most fundamental theoretical questions are not settled. These questions include what is learnable, what does the optimal learning algorithm look like, and what are the characteristics of a problem that enable, or prohibit, learning. This project will explore a new mathematical lens with which to view machine learning, one based in combinatorics, optimization, and the theory of matching in graphs. This perspective promises to unlock answers to the aforementioned questions during the course of this project, and in doing so deepen our understanding of machine learning and guide the search for better algorithmic approaches. In addition to these research goals, the project will include a substantial educational and outreach component. Through research mentoring and new course offerings, the principal investigator will train students at the high-school, undergraduate, and graduate levels in the mathematical fundamentals of machine learning. The principal investigator will also disseminate the ideas and findings of this project through survey articles, tutorials, and presentations, as well as by organizing meetings and workshops to bring together researchers around these fundamental questions. The starting point for this project is the following simple, yet powerful, observation: supervised classification problems can be viewed as a bipartite matching problem on a large, often infinite, graph. This fact follows by re-imagining the one-inclusion graph (OIG) algorithm, an abstraction of optimal learning from the early days of the field, as solving a matching problem. This new perspective allows us to draw on powerful results and tools from combinatorics and optimization to understand the structure of optimal matchings in this graph, and consequently the structure of optimal learning algorithms. Furthermore, generalizing this matching problem beyond classification promises structural and algorithmic insights into supervised learning writ large. This project will tackle the following questions through this new lens: (a) What are the algorithmic recipes for optimal supervised learning? (b) Does this lens help explain the success of common algorithmic approaches, or prescribe new ones? (c) Can we derive structural characterizations of learnability that apply broadly to supervised learning? 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

Understanding how climate has changed in the past (the study of paleoclimatology) can help societies better adapt to and anticipate future climate change. To fulfill this promise, researchers need to have rapid access to the abundance of datasets and analytical methods available to them. Furthermore, they may need assistance in choosing the most appropriate technique(s) for their data, applying them correctly, and interpreting conflicting or ambiguous results. Artificial intelligence (AI), and in particular large language models (LLMs), can help in this regard. Indeed, they have already proven useful as coding assistants. This project develops an artificial intelligent system that uses the power of generative AI while incorporating paleoclimate knowledge. The resulting system, PaleoPAL, is used in the context of three paleoclimate studies to evaluate its effectiveness. In addition, the project engages with publishers to provide guidelines for study incorporating AI assistants in the research. PaleoPAL uses Retrieval Augmented Generation (RAG) to incorporate paleoclimate knowledge (e.g., data, software, methods, workflows, literature) into existing LLMs to create an AI assistant as a Jupyter Notebook, an environment familiar to scientists. This AI assistant helps in the investigation of three paleoclimate problems: placing recent El Niño-Southern Oscillation variations in the context of the last 10,000 years, detecting climate tipping points and their potential precursors, and generating empirically-based, low-cost climate projections. The proposal supports training activities that build capacity in the US workforce, and in particular, teaching a diverse cross-section of the next generation of geoscientists to work with AI assistants, learning from them and challenging them as they would a mentor. This award by the Division of Research, Innovation, Synergies, and Education within the Directorate for Geosciences is jointly supported by the National Discovery Cloud for Climate initiative within the Office of Advanced Cyberinfrastructure within the Directorate for Computer and Information Science and Engineering. 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.