University Of Wisconsin-Madison

NSF Awards · FY 2025 · 2025-05

Stochastic generative models are a cornerstone of applied statistical modeling and inference. A generative model is an abstraction, and often a simplification, of a data generating mechanism using probabilistic tools, where specific features of interest regarding the generating mechanism are encapsulated into parameters of the generative model. Bayesian statistical inference is a popular statistical paradigm for combining such generative models for data with prior information about model parameters in a principled fashion to perform statistical inference on the unknown parameters. Some of the salient aspects behind the tremendous growth in popularity of Bayesian inference include principled incorporation of domain information, an in-built penalty for model complexity allowing automatic model selection, and facilitating borrowing of information across different domains via hierarchical modeling. However, being inherently model-based, Bayesian statistics is intrinsically susceptible to departures from the postulated generative model. Through this project, the investigators will explore and develop new statistical methodology for performing Bayesian inference allowing flexible departures from the generative model under consideration. A major focus will be the user-friendliness of the proposed approaches, circumventing the need for a user to explicitly build probabilistic models of increasing richness. The research will be disseminated through articles at prominent avenues and research presentations. Additionally, software packages for the methods developed will be made available publicly. The investigators are committed to enhancing the pedagogical component of the proposal through advising students and developing graduate and undergraduate topic courses. Flexible nonparametric Bayesian methods have gained in popularity to address perceived issues of traditional Bayesian modeling regarding model-misspecification. The last thirty years have seen a proliferation of such methods, both in mainstream statistics as well as the machine learning community, as we continue to encounter increasing levels of complexities in modern datasets. However, nonparametric Bayesian methods can be challenging to implement as well as interpret. Furthermore, in many applications, the targets of interest are quite simple and it is essentially futile to model all aspects of the data. The fundamental aim of the proposed research is to develop a flexible Bayesian non-parametric approach that retains the generative modeling aspect of traditional parametric Bayesian modeling while avoiding a complete probabilistic specification of the data generating mechanism as typically performed in nonparametric Bayesian modeling. This will be performed by defining a modified likelihood function, leveraging ideas from the empirical likelihood literature as well as optimal transport theory, that centers around a user-specified parametric family of densities. An automated calibration procedure will be developed to control the extent of centering around the parametric model. The investigators will offer a firm theoretical underpinning of the proposed procedure and develop computationally efficient algorithms to carry out inferential tasks. The developed methods will be applied to scientific learning problems in neuroscience and nuclear physics to allow departures from existing scientific models in situations where their operating characteristics are less understood. 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

The Midwest Thermodynamics and Statistical Mechanics (MTSM) Conference is a regional event that brings together early-career researchers to discuss how the behavior of tiny particles (molecules) affects things we can see and use in the real world. Topics include energy storage, environmental protection, materials design, and using biomolecules for drug delivery. The two-day event is a great chance for undergraduate students, early graduate students, and students from schools that don’t focus on research to share their work with others in the science community, without the high costs of big conferences. For many, it’s their first time at a scientific conference, which helps them improve their communication skills, expand the reach of their research, and learn new ideas and questions from others in the field. It also gives them a chance to build connections with other students, professors, and professionals from both academia and industry. The MTSM conference promotes the exchange of new research and ideas among researchers working in different research fields whose core focus is thermodynamic behavior. Research areas include self-assembly, phase transitions, macromolecular dynamics, and macroscopic material properties, encompassing experimental, theoretical, and computational thermodynamics and statistical mechanics. The conference will comprise one keynote lecture by a senior scientist, five invited talks by early-career faculty, contributed talks from graduate students and postdocs, and contributed talks from undergraduate researchers. Participants also will be encouraged to present their work during a poster session. A point of focus for this year's invited talks will be the use of statistical mechanics to study phase behavior and transitions. Entropic forces are often crucial in the formation of materials whose molecular order is intermediate between crystals (having perfect order and reduced entropy) and liquids (having high degree of disorder and high entropy), such as liquid crystals, plastic solids, elastomers, gels, micro-segregated phases of block copolymers, and biomolecules with ordered domains like proteins. The conference will include several networking sessions to give opportunity for scientific discussion. The modest size of the MTSM conference ensures that attendees will be able to interact personally with faculty members from various research institutions, talk with other students doing similar work, and receive valuable feedback. 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 · 2025-05

PROJECT SUMMARY Multidrug-resistant (MDR) bacterial infections have emerged as an urgent global public health threat. The ESKAPE pathogens, comprising six virulent MDR bacteria, are major contributors to life-threatening nosocomial infections. Traditional antibiotic therapies are becoming increasingly ineffective due to the emergence of antibiotic resistance and the stagnation of new antibiotic development. Therefore, there is an urgent need for innovative non-antibiotic antimicrobial approaches to combat these MDR pathogens. To meet this urgent need, we developed an innovative nanoimmunotherapy mediated by a novel red blood cell membrane (RBCM)-coated hemoglobin (Hb)-encapsulating nanoparticle saturated with oxygen (termed RHNP). RHNP functions by sensitizing bacteria to host oxidant killing while simultaneously recruiting neutrophils and enhancing their oxidant killing capability. Our preliminary studies have shown that this approach was highly effective in treating antibiotic- resistant bacterial infections in several mouse models. The objective of this project is to further develop RHNP to achieve broad-spectrum antimicrobial capability against Gram-negative MDR ESKAPE bacterial pathogens, including carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Klebsiella pneumoniae (CRKP), and MDR Pseudomonas aeruginosa (MDRPA). We hypothesize that (1) RHNP can offer a broad- spectrum non-antibiotic immunotherapeutic approach for combating MDR bacteria, and (2) RHNP can exhibit synergistic effects with conventional antibiotics. In Aim 1, we will design, fabricate, characterize, and optimize the RHNP. We will optimize the RHNP formulation (i.e., Hb-cholesterol (Chol)@RBCM NP) by optimizing the ratios of Hb/Chol and RBCM/Hb-Chol. RHNPs will be fabricated via both a batch and a continuous process. RHNPs with desirable physiochemical characteristics and biocompatibility will be identified for studies described in Aims 2 and 3. In Aim 2, we will first examine the antimicrobial efficacy and mechanisms of RHNP in treating the MDR planktonic bacteria. We will then study the synergistic effects and synergistic mechanisms of RHNP/antibiotic combination therapy against MDR planktonic bacteria. Subsequently, the antimicrobial efficacy of RHNP with or without antibiotics against bacterial biofilms will be investigated. In Aim 3, we will study the therapeutic efficacy of RHNP alone or in combination with antibiotics in three rodent infection models representing different healthcare-associated infections. The effects of neutrophils and macrophages on the therapeutic outcome will also be assessed to further clarify the immunotherapeutic mechanisms. The safety of RHNP will be evaluated by hematological and biochemical parameters, inflammatory cytokines, and organ histopathology in mice. RHNP represents a transformative approach to treating MDR infections, offering a universal, safe, and effective immunotherapy option. Its potential to enhance the effectiveness of existing antibiotics could also transform current antibiotic treatment protocols. This project has the potential to save countless lives and will significantly alleviate the burden on healthcare systems worldwide.

NSF Awards · FY 2025 · 2025-05

Xuhui Huang of University of Wisconsin, Madison and Pengyu Ren of University of Texas, Austin are supported by an award from the Chemical Theory, Models and Computational Methods program in the Division of Chemistry to develope a new polarizable implicit solvent model for efficient and accurate RNA modeling. RNAs play a key role in regulating gene expression and many other vital cellular processes. Understanding how RNAs bind and fold is key to uncovering their molecular mechanisms and advancing RNA-based molecular design. Traditional molecular dynamics (MD) simulations, which do not account for electronic polarization, often fail to accurately model highly charged RNAs. In particulalr, water molecules, being highly polarizable, behave differently near these charged RNAs compared to in bulk water. In addition, explicit sovent based MD simulations are computationally expensive. To address these chanllenge, Huang and Ren will develop a new polarizable solvation model that represents water molecules around RNAs implicitly through statistical descriptions of water density and correlations. This model will adapt to changes in the local electrostatic environment, ensuring high efficiency and accuracy in modeling RNAs. Huang and Ren will apply this model to study RNA hybridization, RNA-small molecule binding, and ion-induced RNA folding. As part of the educational and component of this project, they will integrate their research findings into undergraduate and graduate courses to enhance STEM education. The developed software will be publicly available through the TINKER software package on GitHub and training workshops will be organized to educate the scientific community on the efficient use of the software. Compared to the explicit solvent models, the 3-Dimensional Reference Interaction Site Model (3DRISM) simplifies the all-atom description of solvation into a density-based representation of the solvent surrounding the solute. 3DRISM eliminates the need to sample explicit solvent configurations and enables the explicit inclusion of ions (e.g., Mg²⁺), which are crucial for accurate RNA modeling. However, current 3DRISM solvent models rely on pair correlation functions and cannot explicitly account for the many-body response in solvent. To overcome these limitations, Huang and Ren will develop a polarizable-3DRISM (p3DRISM) implicit solvent model to accurately model polarizable solvation for polarizable AMOEBA solutes. First, Huang and Ren will derive a new form of the 3DRISM equation that incorporates solute-solvent-solvent 3-body correlations and will develop an efficient implementation of this new equation, based on linear response theory. This approach accounts for changes in solvent-solvent correlation functions induced by polarization from the local electric field. Secondly, they will incorporate polarizable solute-solvent interactions through induced dipoles in the p3DRISM scheme. Huang and Ren will apply AMOEBA-p3DRISM to calculate free energies for RNA hybridization and RNA-small molecule binding, as well as to model Mg²⁺-induced folding of RNA k-turns. The software and algorithms developed will benefit the pharmaceutical and biotech industries, especially in RNA-based therapy and computer-aided drug discovery. Additional broad impacts include outreach to undergraduates at University of Wisconsin, Madison and University of Texas, Austin, integration of research findings into coursework, and training workshops for the scientific community. 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 program is a renewal for the REU site at the University of Wisconsin-Madison, a program that has been active for more than two decades. This program aims to provide foundational, hands-on research experiences to undergraduates from across the nation who otherwise would have no access to research opportunities at their home institutions. By working together with experienced research mentors at the University of Wisconsin-Madison, undergraduate students will gain hands-on expertise at the forefront of science, giving them the tools to reach their full potential in their careers. Furthermore, a close and personal collaboration between students and experts will yield new scientific discoveries. The training offered by this program will have a positive, long-lasting impact on the future professional trajectories of undergraduate students. This Research Experience for Undergraduates program will build upon the more than two decades of expertise at the University of Wisconsin-Madison to provide a 10-week long hands-on research training and experience to eight students each summer. Research topics are centered around current open questions in astrophysics, with particular emphasis on studies of planets around other stars as well as multi-messenger astrophysics, to address some of humanity’s eternal questions: How did the Universe evolve, and what are the origins of life in the Universe. The program includes a lecture series in astrophysics, training in research methods communication, and computing techniques to prepare students for the ongoing data revolution using techniques such as machine learning and A.I. Additional career preparation is provided through professional development seminars, field trips to nearby national research centers, as well as opportunities to engage in public outreach to disseminate new scientific insights with society. 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

The ability to convert long-wavelength infrared (IR) light to electricity has become important for a number of current and emerging technologies, including thermophotovoltaics for waste or primary energy conversion, IR power beaming, and IR photodetectors. A key barrier to many applications, however, is the availability of high-performance photovoltaic cells tailored to these wavelengths of light. Current technologies exhibit insufficient performance and high cost due to material and fabrication limitations. One possible way to address these challenges is to use nanoscale quantum structures in the photovoltaic cell, in a way similar to some commercial photodetectors. This could allow the use of more common materials and reduce some of the losses that limit performance. However, these quantum structures have not been studied in detail for power generation, and a number of open questions exist about how they function and perform. This project will study the fundamental operation of quantum-structured photovoltaic cells, fabricate these types of devices, and measure their performance. This research could have direct impacts in several energy applications, which could help the U.S. reduce reliance on foreign energy sources and improve infrared technologies for a variety of power, communications, and defense applications. This project also seeks to advance the U.S.’s expertise in semiconductor technologies by inspiring students to join the semiconductor workforce and creating new initiatives for graduate and undergraduate students to explore these career options. The goals of this project are to: (1) determine the influences of bias and illumination on band structure and carrier transport, and identify design strategies to achieve high carrier collection under forward bias; (2) identify nanophotonic structures to couple IR radiation into the active region of these devices while minimizing parasitic absorption; and (3) fabricate cells with narrow intersubband gaps and demonstrate high energy conversion efficiencies while improving modelling and understanding of transport. The research will utilize a combination of quantum optoelectronic simulations to investigate the band structure and electronic transport under illumination and bias, finite element electromagnetic simulations to design photonic structures for coupling light into the ISPV cell, custom models to predict device performance, epitaxial growth of novel types of conduction band engineered active regions and test samples via metalorganic chemical vapor deposition, microfabrication of samples and devices, and detailed material and device characterization using standard and custom spectroscopy, microscopy, and testing equipment. This work will develop a detailed understanding of the relationships between materials, structure, transport, and device performance for an intersubband quantum cascade structure under illumination and in use for electricity generation. Preliminary results indicate that the structure of an intersubband photovoltaic cell is likely to be quite different from a traditional quantum cascade detector, and this research will reveal why these types of structures are different and how an active region should be designed for effective power generation. The combination of experimental and simulation activities and parallel investigation of semiconductor structure and photonic structure will lead to strong platform for future design of scalable and efficient IR energy conversion devices in a variety of applications. 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

The project investigates how war-induced relocation affects the professional, social, and civic life of physicians. Through a case study approach, this research examines the factors that facilitate or hinder their continuation of medical practice, integration into the host region, and participation in civic life when physicians are relocated. By understanding these dynamics, the study aims to enhance scientific understanding of how highly-skilled professionals displaced by war can contribute to their host regions and whether shared professional or civic identities help overcome war-induced divisions. Physicians are considered a prototypical professional group due to their universal commitment to care, reliance on scientific knowledge, and pursuit of autonomy. Core data collection includes in-depth, semi-structured interviews with clinicians who relocated during the last decade. To assess the role of pre-existing professional communities in facilitating integration, additional interviews are conducted with physicians who relocated from the same areas several decades ago. Virtual interviews also are conducted with physicians who remained in conflict-affected regions to gain insight into their perceptions of and connections with colleagues who left. Data are analyzed using abductive reasoning, and a database of relevant organizations, social networks, and media is developed to support the analysis. The research is conducted by a collaborative team under the NSF/BSF program. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Acute laryngeal injury (ALgI) occurs in over 50% of patients after intubation and mechanical ventilation. ALgI is associated with significantly worse voice, breathing, and swallowing months after extubation. ALgI results from endotracheal tube pressure on the posterior glottis, leading to ischemic mucosal injury that progresses to glottic scar and debilitating phonatory insufficiency or life-threatening narrowing of the glottic airway. Glottic stenosis is managed with tracheostomy or destructive surgery sacrificing vocal quality for airway patency. There is a critical need for focused scientific approaches to identify key elements of pathologic wound healing following intubation-related laryngeal injury for the development of novel precision therapeutics. Studies of patients with post-intubation tracheal stenosis have implicated impaired epithelial barrier function, which leads to microbial infiltration into the tissue lamina propria, dysregulated adaptive immunity, and pathologic T-cell-fibroblast interactions that drive excessive extracellular matrix production. However, glottic stenosis is different, with severe functional implications of even minor scarring of the unique glottic anatomy. There is a significant knowledge gap regarding the pathophysiology of intubation-related glottic injury, and therefore a lack of evidence-based approaches to optimize wound healing to prevent scar. The PI has identified clinical bacterial culture positivity in 75% of human ALgI specimens, with Staph aureus most commonly isolated.1 Persistent antigenic stimulation, such as in chronic infection, is known to induce sustained immune cell activation. The PI has measured increased T-cell infiltration and activation in patients with post-intubation tracheal stenosis, however the T-cell response following glottic injury is poorly characterized. Dysbiosis (imbalanced microbial composition) and its impact on the immune response have been linked to the progression of pulmonary fibrosis, however, a relationship among dysbiosis, immune activation and fibrosis has not been evaluated in glottic scar. In this study, we will determine the effect of dysbiosis-mediated immune activation on glottic scar formation in humans (Aim 1) and a novel murine model (Aims 2-3). In Aim 1 we will employ single-cell RNA sequencing and 16S rRNA sequencing to determine the impact of dysbiosis and immune activation on the formation of glottic scar in patients following laryngeal injury. In Aim 2, we will establish the role of microbiome-induced immune activation in the development of glottic scar by comparing laryngeal wound healing in germ-free and conventionally raised mice. Finally, in Aim 3 we will evaluate the impact of pathogenic bacteria and therapeutic microbiome modulation on the formation of glottic scar using the gnotobiotic mouse model.

NIH Research Projects · FY 2025 · 2025-05

PROJECT SUMMARY The retina faces the considerable challenge of continuously and reliably encoding a wide dynamic range of light intensities. At the first two synapses of the retina are ribbons, large planar structures often described as ‘conveyer belts’ that continuously supply active zones of release with glutamate vesicles. As such, ribbons are thought to mediate high rates of glutamate release that allow for dynamic encoding of visual stimuli. In the retina, visual information flows from photoreceptors to bipolar cells to ganglion cell (GC) output neurons that send information to the brain in the form of spikes. In mice, there are at least 40 functionally distinct retinal GCs, each tuned to different features of the light environment and exhibiting unique circuit organizations. Therefore, our understanding of how the retina informs the brain is based on understanding how ribbons mediate the transfer of visual information through retinal circuits to shape GC output. The goal of this project is to determine how the function of two different GCs—ON-sustained and OFF-sustained alpha—are shaped by ribbons. As lighting conditions change, glutamate release probability at ribbon synapses is dynamically adjusted to match sensitivity needs—termed light adaptation. However, whether ribbons are directly responsible for regulating glutamate release during light adaptation is unclear. To answer this question, by measuring synaptic inputs to ON-sustained and OFF-sustained alpha GCs in a ribbon loss-of-function (Ribeye-ko) mouse model, I will first determine if ribbons regulate two forms of glutamate release that are thought to be important for adaptation: multivesicular release (MVR), the simultaneous release of multiple vesicles, and synaptic depression, a transient reduction in release probability following a stimulus. I will then use more dynamical stimulation methods to test whether ribbons set the time-course of adaptation to changes in luminance (mean light intensity) and contrast (variance about the mean) in GCs. Finally, I will identify how ribbons contribute to the formation of GC synaptic inputs using near-infrared branding and electron microscopy, thus correlating structure to function. GCs possess receptive fields that integrate information across space and enable the detection of specific features of the visual scene, such as edges, texture, or motion. Such spatial integration is contingent on tunable excitatory inputs to GCs, raising the possibility that ribbons are key determinants of the emergence of certain receptive field properties. To test this, using the Ribeye-ko model, I will measure excitatory synaptic inputs and spike outputs of ON-sustained and OFF-sustained alpha GCs in response to spatial stimulation paradigms that probe basic receptive field properties, including center-surround organization, nonlinear spatial integration, and feature sensitivity (i.e., to stimuli that exhibit texture or motion). I will complement functional studies with measurements of circuit anatomy, including presynaptic bipolar cell morphology and the organization of synaptic inputs, to both GC types via two-photon and confocal microscopy. This combinatorial structure-function approach will allow me to disentangle how ribbons shape overall circuit organizations.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY/ABSTRACT Zebrafish provide a valuable model system for studying developmental and regenerative biology. Recent advancements in genome editing techniques enable the generation of knock-out alleles in zebrafish, expanding the usefulness of this model organism to interrogate loss-of-function study. However, the majority of genome editing-mediated mutants in zebrafish consist of conventional loss- of-function mutants rather than more sophisticated alleles, such as conditional loss-of-function alleles. Thus, a critical obstacle in zebrafish research lies in the functional dissection of genes within specific cell types and during later development stages. A reliable and definitive conditional loss-of-function system that has been utilized extensively in other organisms is Cre/lox-mediated gene disruption. Although this Cre/lox system is functional in zebrafish, creating reliable floxed alleles has remained challenging. This proposal aims to address the existing limitations in conditional genetics within the zebrafish model by developing a robust and effective methodology. In Aim1, we will establish a synthetic exon-mediated integration approach, allowing the addition of two loxp sites into the target gene within a single generation. We will compare our strategy with the previously published method to assess efficiency. Our study will establish the effective method to generate reliable floxed alleles. Combined with CreER lines, these floxed alleles will enable conditional knock-out of target genes at a predefined time and/or in discrete cells, facilitating investigation of intricate cellular and molecular mechanisms. Advancements in base and prime editing techniques enable to introduce human disease- causing mutations into the zebrafish genome, significantly promoting the application of zebrafish for human disease modeling. However, the current base and prime editing approaches rely on PCR-based screening to identify lines carrying the edited genome. Given the low efficiency of base/prime editing and a reduced germline transmission rate, the current screening method may fail to select positive fish due to the complicated multiple steps for genotyping. In Aim 2, we will expand our synthetic exon- mediated genome editing approach to develop a proficient and highly effective method for editing amino acid changes in zebrafish. We will combine a synthetic exon approach with a robust fluorescence- based screening strategy to dramatically reducing screening effort for introducing amino acid change. Overall, our methods, lines, and reagents will save years of research time in developing diverse zebrafish genetic models that can open new research avenues within the zebrafish community.

NSF Awards · FY 2025 · 2025-05

With the support of the Chemical Catalysis program in the Division of Chemistry, Professors Daniel Weix and Shannon Stahl of the University of Wisconsin-Madison, Professor Mohammad Rafiee of the University of Missouri-Kansas City, and Professor Robert Paton of Colorado State University are studying new approaches to catalysis and electrochemistry for the synthesis of biaryl molecules useful in polymers and agriculture. Building upon their recent advances, this team will continue to develop analytical and computational tools that will be used to illuminate fundamental principles that are important for success of these catalytic reactions. The lessons learned will enable lower-cost, higher-efficiency synthesis of important molecules using electricity in place of metal reductants. The research team will also work to train the next generation of chemists via several established programs and to educate the broader chemistry community about organic electrochemistry via courses and lectures. This project focuses on electrochemistry-driven and nickel-catalyzed reductive biaryl synthesis from a variety of aryl electrophiles. The research team will use a combination of stoichiometric organonickel studies, theory, and electroanalytical techniques to understand how each step in the biaryl synthesis (oxidative addition, transmetalation, reduction, and reductive elimination) is influenced by catalyst identity, conditions, and applied potential. This understanding will be used to make electrochemical biaryl synthesis suitable for commercial scale-up by conducting additional studies to improve catalyst turnover number, turnover frequency, and selectivity, including the development of cross-selective reactions. More broadly, these studies will contribute to an improved understanding of nickel catalysis and electrosynthesis; the resulting reactions will be lower-cost, more efficient alternatives to the state-of-the-art biaryl syntheses, which may utilize less selective oxidation reactions, more expensive precious metal catalysts, and/or more reactive aryl nucleophiles. 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 · 2025-05

PROJECT SUMMARY With this R13 application, we request funding to support, in part, the costs for planning, publicizing, and hosting the 42nd, 43rd, and 44th Annual Symposia on Nonhuman Primate Models for AIDS. For more than four decades, this symposium has served as the premier scientific forum for the exchange of information, including new research findings and scientific perspectives, among HIV/AIDS investigators whose research includes studies in nonhuman primates (NHPs). Disseminating the latest research findings in NHP models of AIDS while also facilitating discussion and exchange of information between basic scientists and clinicians remains a priority, as do focusing on emerging technologies to accelerate translation of NHP studies into the clinic and engaging a broader and more diverse group of researchers in HIV/AIDS research in NHP models. This meeting, the only one of its kind in the world, convenes an international group of scientists whose research focuses on the study of natural and experimental immunodeficiency virus infections in NHPs, as well as on the development of novel therapeutics, prophylactic vaccines for HIV, and curative approaches. Emerging topics in related infectious diseases (such as COVID-19 pathogenesis, vaccines and treatment) may also be included. The seven National Primate Research Centers (NPRCs) host this meeting in rotation, and upcoming symposia hosts will be the Wisconsin (2025), Southwest (2026), and Washington (2027) NPRCs. We plan a hybrid format with most participants attending in person and others joining online to access oral and poster sessions. The conference will begin on day 1 with registration, a keynote address by a leading HIV/AIDS researcher, and an evening reception. The following two and a half days will include scientific presentations from invited speakers and accepted oral abstracts. Each symposium scientific committee will select session topics and speakers to highlight new and cutting-edge technologies in their respective fields. Each session will open with a 30-minute talk by an invited chair. Individuals whose abstracts are accepted for oral presentations will give the remaining session talks. A poster session will occur on the evening of day 2, and there will be a banquet on the evening of day 3. As is traditional for this symposium, the Journal of Medical Primatology will publish all poster and oral abstracts in a special issue. In partnership with the HIV Vaccine Trials Network (HVTN), the NHP AIDS Symposium will also host a pre-symposium meeting for early-stage investigators (ESI). This meeting will be open to the attendees of a linked ESI Conference the HVTN sponsors. ESI attendees and mentors will focus on grant writing, budgeting, and networking, and will participate in a Q&A with NIH Program Officers. We believe bringing together researchers from a variety of diverse backgrounds will generate future collaborations and scientific advances. Knowledge shared and gained at upcoming Annual Nonhuman Primate Models for AIDS Symposia will further the continued, effective use of NHP models to maintain long term control of HIV replication in the absence of antiretroviral therapy and to design interventions to prevent or eradicate HIV infection.

NSF Awards · FY 2025 · 2025-05

With the support of the Chemical Synthesis Program in the Division of Chemistry, Professors Jennifer Schomaker and Jeffrey Martell of the University of Wisconsin-Madison and Dr. Jing Chai at GSK are advancing DNA-encoded chemical library (DECL) technology to prepare and screen new compounds with potential bioactivity against diseases untreatable with known pharmaceuticals. DECLs are synthesized by tagging chemical precursors with small, unique fragments of DNA to ‘bar-coded’ the precursors. These are then reacted in a combinatorial fashion to generate millions-to-billions of novel chemical entities for testing against previously ‘undruggable’ proteins. While this strategy is low-cost and efficient, a major drawback is the inability of fragile DNA tags to tolerate oxidation conditions, which restricts the diversity of the resulting compound libraries. To address this challenge, the Schomaker and Martell teams are developing mild oxidative reactions that preserve the integrity of the DNA, significantly broadening the scope of drug candidates that are made with DECL technology. They are also investigating how altering the positioning of DNA barcodes influences library preparation and their resulting bioactivity. Drawing on their combined expertise, the team is designing innovative on-DNA oxidations catalyzed by Earth-abundant metals, such as copper. From a training perspective for young scientists, UW and GSK are creating a two-week summer course on the syntheses, analyses and applications of DECLs to encourage academic researchers to adapt their new synthetic methods to the preparation of novel drug libraries. The theory portion of the course surveys the benefits of DELC for drug discovery and highlights the challenges of conducting chemistry on DNA, while the hands-on portion focuses on the manipulation, synthesis and analyses of DNA-linked organic compounds. This proposal brings together expertise in reaction methodology (Schomaker), use of non-genomic DNA to construct hybrid catalysts to accelerate reactions (Martell), and capabilities in analytical chemistry, molecular biology and informatics (Chai, GSK) to advance the power of DNA-encoded chemical libraries (DECLs). Typical approaches to prepare large (> 1,000,000), unique compound libraries cost millions-to-billions of dollars ; however, DECL technology, which combines DNA barcoding with high-throughput chemistry, enables the creation and screening of billions of compounds at a fraction of the usual cost. A big challenge in expanding the scope of DECLs has been the lack of viable oxidative transformations that can be conducted on DNA, as DNA barcodes often degrade under oxidative conditions. This GOALI collaboration between GSK and UW-Madison is developing powerful oxidative methods for on-DNA library synthesis to expand the structural diversity and Fsp3 of current drug screening libraries. The goals of this collaboration are: 1) developing three-component oxidative cyclization reactions on DNA, 2) merging on-DNA Cu-mediated oxidation with three-component click reactions to expand DEL diversity, and 3) creating DNA-scaffolded catalysis for efficient oxidation reactions with minimal damage to DNA. Significance and broader impacts of this work stems from: 1) developing complexity-generating oxidative methods that are successfully conducted on DNA, 2) applying new methods to generate novel DELs that expand GSK’s bioactive/therapeutic chemical space, 3) providing new drug candidate leads with improved bioactivity, efficacy and ADMET properties to the broader community, and 4) validating methods for the analyses of DECL able to utilize shared instrumentation in academic settings. GSK and UW are establishing freely accessible protocols for the community by creating a two-week workshop on the theory and practical aspects of DNA-encoded library construction, analysis and screening to encourage other academic labs to adopt this technology. 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 Toll/interleukin-1 receptor (TIR) domains, conserved from archaea to mammals, mediate innate immune signaling. Multiple bacterial pathogens use secreted TIR domain-containing effectors to modulate hostpathogen interactions and sabotage host immunity. Recently, bacterial TIR domains were discovered to have nicotinamide adenine dinucleotide (NAO+) hydrolase activity, depleting host cell NAO- during infection. Since NAO- levels regulate metabolism, cell signaling and immune function, bacterial TIR-mediated NAO- hydrolysis is potentially highly relevant for infectious success. However, the role of TIR-NAOase activity in bacterial pathogenesis remains unknown. This proposal will address this knowledge gap, focusing on Bruce/la species that are highly pathogenic for humans as a model system. We will test the overall hypothesis that TIRmediated NAO' hydrolysis directly contributes to bacterial virulence. Aim 1 will determine if TIR-NAO' hydrolysis contributes to the immunosuppressive properties of Bruce/la TIR domain-containing effectors BtpA/BtpB by assessing the inhibition of host cell NF-KB activation and inflammatory cytokines in infected primary macrophages and dendritic cells. This aim will also localize the BtpA/B effectors in infected cells and determine if the TIR-NAOase activity contributes to the targeting of host TLR-adaptor complexes. Aim 2 will establish the role of the BtpA/BtpB TIR-NAOase activities in vivo. Using TIR-NAOase catalytic mutants, splenic inflammation will be quantified in a standard BALB/c murine model of brucellosis. Additionally, the contribution of NAOase activity to virulence will be assessed in a newly developed, completely penetrant, and clinically scorable SKG model of Bruce/la-induced spondyloarthritis, the most common chronic complication of human brucellosis. This project is innovative as it will establish the relevance ofTIR-mediated NAO' depletion in the context of mammalian infection, both in vitro and in vivo. Moreover, this work will validate a new model of Bruce/la-induced spondyloarthritis and its use for dissecting the bacterial mechanisms implicated in chronic brucellosis, for which no model is currently available. The proposed work is highly significant and aligns with the mission of the NIH in that it will define the mechanisms of host immune evasion by this important family of bacterial secreted effectors, potentially resulting in a paradigm shift in our understanding of how bacterial TIR domains contribute to host-pathogen interactions and pathogenesis. The results generated will have a broad impact given the number of bacteria associated with human infectious diseases containing TIR-effector proteins with NADase activity. Finally, targeting TIR-NADase activity may offer a promising new therapeutic approach for infectious diseases.

NIH Research Projects · FY 2026 · 2025-04

Project Summary/Abstract Mechanical stimuli play a major role in the regulation of skeletal muscle mass and the maintenance of muscle mass significantly contributes to disease prevention and quality of life. While the link between mechanical stimuli and the regulation of muscle mass has been appreciated for decades the exact mechanisms that control this process remain poorly defined. Current models assert that mechanically induced increases in muscle mass are driven by a positive shift in the balance between protein synthesis and degradation which, in turn, leads to the net accumulation of newly synthesized proteins and muscle growth. Work from our lab and others has identified the mechanistic target of rapamycin complex 1 (mTORC1) as a major regulator of this process, however, little is known about the upstream pathway(s) that control the activation of mTORC1 and/or related events that potentially contribute to the mechanical regulation of protein synthesis and growth. In an effort to identify these pathway(s) our lab recently performed a phosphoproteome-wide analysis of the signaling events that occur in response to endurance and resistance exercise in humans. The rationale behind this study was based on the recognition that resistance and endurance exercise lead to very distinct muscular adaptations with endurance exercise promoting an increase in aerobic capacity whereas resistance exercise induces an increase in protein synthesis and growth. Thus, we reasoned that our analyses would lead to the identification of signaling events that are activated specifically by endurance and resistance exercise. We were particularly interested in the resistance exercise-specific signaling events because these would represent potential members of the upstream pathway(s) that promote the activation of mTORC1, protein synthesis, and growth. The outcomes of these analyses revealed that mitogen-activated protein kinase kinase 3b (MKK3b) undergoes a prolonged activation following resistance but not endurance exercise and that this event is highly correlated with the increase in myofibrillar protein synthesis following resistance exercise (R = 0.87). Follow-up studies also revealed that the prolonged activation of MKK3b is conserved in a mouse model of resistance exercise and that the activation of MKK3b is sufficient to induce mTORC1 signaling, protein synthesis, and muscle growth. Thus, my overarching hypothesis is that MKK3b is a central component of the upstream pathway via which mechanical stimuli induce the activation of these processes. In the proposed project I will determine whether MKK3b is necessary for the activation of mTORC1, protein synthesis, and muscle growth by employing skeletal muscle-specific and tamoxifen-inducible MKK3b knockout mice, two complementary but distinct models of mechanically induced growth, advanced imaging techniques, and our innovative method for visualizing and quantifying the accumulation of newly synthesized proteins. Collectively, these studies will not only address a major gap in knowledge regarding the mechanism(s) whereby mechanical stimuli regulate muscle mass, but they will also propel me toward my goal of becoming a principal investigator at a research-intensive institution.

NIH Research Projects · FY 2026 · 2025-04

PROJECT ABSTRACT Trading sex for compensation (e.g., money, drugs, alcohol) is a complex public health problem. Significant increases in internet usage have drastically changed the landscape of virtual sex trading (e.g., photos, webcamming). However, our understanding of sex trading is methodologically limited, as it most often relies on a single item, e.g., “have you ever traded sex for money or drugs?” Extant research does not differentiate between sex trading type (e.g., virtual vs. in-person), circumstances (e.g., economic need), compensation type (e.g., money, substances), risks (e.g., unprotected sex, victimization) and protective factors (e.g., harm reduction strategies). We have developed a multi-item sex trading measure to identify sex trading behaviors and their associated compensations, circumstances, risks, and harms. We validated our measure in a sample of university students, and we found that 11% of undergraduate students and 18.1% of graduate students reported at least one sex trading behavior, as compared to 2 to 4.5% of students in prior studies. Therefore, in- person and virtual sex trading may be more widespread and relevant to a larger segment of the population than previously assumed. Guided by the Risk Amplification and Abatement Model, this novel, multi-phase, mixed-methods proposal aims to: (1) adapt our validated sex trading measure for the general population; (2) use the resulting measure to identify the prevalence and associated characteristics (e.g., adverse experiences, substance use, mental health problems, and violence) of sex trading in a nationally representative sample of young adults (ages 18-34); and (3) examine the characteristics of sex trading in a non-probability sample of young people who report having participated in at least one sex trading behavior (ages 18-34). In aim 1, we will conduct 2-3 waves of cognitive interviews with people with who have traded sex to ensure clarity and relevance of our measure for a more diverse general population. In aim 2, we will use our resulting measure to assess sex trading in a nationally representative, probability-based sample (Amerispeak). In addition to reporting the prevalence of sex trading and associated characteristics (e.g., STIs, substance use), we will use Latent Class Analysis (LCA) to examine typologies of sex trading based on acts and associations between the resulting classes and compensation types, circumstances, and consequences. In aim 3, we will use web- based, Respondent Driven Sampling (webRDS) and replicate aim 2’s LCA to understand differences and similarities in sex trading among young adults who report sex trading and are at high risk of adverse outcomes. Data gleaned from these two samples will allow us to understand whether and how circumstances and associated harms differ between those who are captured in a nationally representative sample and those targeted based on identified sex trading, thereby ensuring that the experiences of the most vulnerable are made visible. Findings have the potential to transform our understanding of sex trading, which is needed to advance interventions and policies to support youth across settings.

NSF Awards · FY 2025 · 2025-04

The significance of this I-Corps project is based on the translation from lab to market of a new method for validating artificial intelligence (AI) outputs that will help industries adopt trustworthy and reliable AI technologies. The solution generates calibrated confidence scores, indicating when decision-makers can rely on AI outputs. The fundamental issue this solution seeks to address is how to ensure AI produces trustworthy responses when used in industry applications, making it safer and more practical to use AI systems across different industries. The potential impact of commercializing this technology is more widespread adoption of AI tools in critical situations, enabling decision-makers to act more confidently, especially when time is critical. By bringing this advance to the marketplace, the gap between AI's potential and its real-world use could be bridged, helping ensure U.S. dominance in the AI industry worldwide. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of a novel statistical framework for validating Large Language Model (LLM) outputs in settings where traditional benchmarking is impossible or unreliable due to the lack of data or the presence of human disagreement. The solution employs advanced statistical techniques to quantify uncertainty in AI-generated responses by analyzing patterns of agreement and disagreement between multiple model runs and between models and human experts. The approach differs from traditional model validation methods that require a gold standard for comparison and only offer an average accuracy level, instead of being individualized to the exact output. By generating calibrated confidence scores that correlate with accuracy, the technology enables users to make informed decisions about when to trust AI outputs, even in high-stakes domains requiring significant human judgment like healthcare and finance. 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 · 2025-04

This project supports a two-day meeting for scholars supported by the National Science Foundation (NSF) Cyberinfrastructure for Sustained Scientific Innovation (CSSI) program. This meeting is held jointly with a similar meeting for scholars supported by the NSF Cybertraining and the Strengthening the Cyberinfrastructure Professionals Ecosystem (SCIPE) programs. It will serve as a platform for participants to advance the mission of the CSSI program by 1) exchanging Cyberinfrastructure (CI) advancements created by CSSI Principal Investigators (PIs); 2) share best practices for creating and maturing CI; and 3) creating opportunities for collaboration to advance CI development and utilization by interacting with PIs from the Cybertraining, SCIPE, and other NSF communities. The two-day meeting for scholars supported by the National Science Foundation CSSI program will share innovations and best practices for the development of sustainable cyberinfrastructure (CI) among critical stakeholders, including the Cybertraining community, SCIPE community, CSSI community, and Computational and Data-enabled Science and Engineering (CDS&E) community. These workshop interactions will support the continued development of CI to advance science and engineering, and to broaden the nation’s CI portfolio. These impacts will be assessed by various metrics in a final report, which will be disseminated to participants and available through public services. 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/ABSTRACT Dopamine is a monoamine neuromodulator that is critical for the regulation of complex behaviors in the human brain. Dysregulation of dopaminergic neurotransmission has been implicated in a spectrum of psychiatric disorders, including attention deficit hyperactivity disorder (ADHD), bipolar disorder, and schizophrenia. Moreover, a substantial proportion of psychotropic medications, most notably antipsychotics, exert their therapeutic effects through the modulation of dopamine signaling. Elucidating the molecular, cellular, and physiological underpinnings of the human dopaminergic system will be essential in the development of novel and targeted therapeutic interventions for psychiatric illnesses. Recently, our lab has uncovered a population of inhibitory interneurons in the cerebral cortex that although present in non-human primate species, display unique molecular features in humans. We found that in humans, but not other mammalian species, these interneurons express the key components of dopamine synthesis and are capable of producing and releasing dopamine. Importantly, we identified that dopaminergic interneurons are completely absent from the cerebral cortices of our closest living relatives, the nonhuman African great apes (chimpanzee, bonobo, and gorilla species). These observed differences in the abundance of dopaminergic interneurons between species, along with their distinct molecular profile in the human cortex, suggests a human-specific role for these neurons within neocortical circuits. However, fundamental questions on the development and function of these interneurons remain unanswered. The objective of this proposal is to unravel the functional properties of human cortical dopaminergic interneurons and to identify the developmental and evolutionary mechanisms underlying the selective absence of dopaminergic interneurons in the cerebral cortices of nonhuman African great apes. To accomplish this, we will use human and chimpanzee stem cell-derived brain organoids to model developmental dynamics of brain development and assess the function of dopaminergic interneurons with simultaneous profiling of electrophysiology and transcriptomics in single cells (Patch-seq). The proposed experiments stand to significantly deepen our mechanistic and physiological understanding of a highly-derived neuronal subtype in the human cerebral cortex. Unraveling the function of cortical dopaminergic interneurons as well as the developmental and evolutionary mechanisms that underlie these functions will provide crucial insights into the human dopaminergic system and identify putative targets for intervention in dopamine-associated psychopathologies. In addition to this research, my training with the University of Wisconsin Medical Scientist Training Program will provide an exceptional foundation in the technical skills, responsible conduct of research, leadership, and clinical expertise to become a successful independent physician-scientist in Child and Adolescent Psychiatry.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY/ABSTRACT The social costs of child abuse and neglect are staggering, with the lifetime economic burden of one year of child protective services (CPS) cases reaching an estimated $592 billion. It is well-established that low- income and poverty are strongly correlated with CPS involvement. Studies have shown that increasing income is associated lower rates of CPS involvement, with some evidence that this relationship is causal in nature. Yet, this research is limited in two critical aspects. First, all the causal studies to date evaluate the effect of additional income received from work-conditioned income via tax credits, meaning that the additional income is conditional upon parental employment. Economic theory suggests that income received via unconditional tax credits should lead to lower rates of CPS involvement because it can increase parental investments without decreasing parental time with children and because the most disadvantaged under- and unemployed parents are categorically excluded from existing work-conditioned credits. Second, as minoritized families are disproportionately both involved with CPS and un- or under- employed, a key question is whether the effects of unconditional cash transfers reduce well known racial disparities in CPS involvement. Our team’s recent microsimulation study found that an unconditional cash transfer would nearly eliminate racial disproportionality in CPS involvement. Yet, the average and race- specific causal effects of unconditional cash transfers on CPS involvement and the mechanisms underlying this relation remain unknown. That is the gap our proposed research aims to fill. To answer this question, we propose to evaluate the effects of the unconditional income received by families as part of the 2021 American Rescue Plan Act expanded child tax credit (CTC), the nation’s first monthly child allowance-type unconditional cash transfer. We innovate by using population-level linked administrative data that will enable us to longitudinally observe CPS involvement and other aspects of objective child health and safety, including relatively rare outcomes, and many parent- and child-level mechanisms that plausibly underlie this relationship. Aim 1 evaluates the effect of an unconditional cash transfer via the expanded CTC on CPS involvement and other objective measures of safety and wellbeing among infants. Aim 2 considers the CTC’s effects on children ages 1 to 17 and Aim 3 tests for racial/ethnic differences. All three aims include an exploratory analysis of mechanisms. This study will provide the first rigorous evidence for policymakers and practitioners on the value of unconditional cash income to reduce CPS involvement and reduce racial disparities therein. Our results will shed light on the nuances in poverty policy design that are imperative for equitable transmission of health and safety for children, providing novel insight into the ways that economic supports do or do not reduce racial disparities in CPS involvement.

NIH Research Projects · FY 2026 · 2025-03

Abstract The full collection of T-cell receptors within an individual, their TCR repertoire, provides critical insight into and information about the individual's ability to mount any kind of T-cell response. This response can be helpful or harmful, ranging from eradication of an infection or destruction of cancerous cells to an auto-immune attack on the body itself. Technologies have recently been developed that allow for TCR profiling in individual cells providing opportunity to identify rare clonotypes and characterize the TCR repertoire at unprecedented levels of resolution. Unfortunately, much of the potential has yet to be realized as statistical methods to analyze high- throughput TCR-seq data are lacking. This proposal addresses some of the most critical statistical deficiencies that are currently preventing the scientific and clinical communities from turning valuable high-throughput TCR profiling measurements into meaningful results. In particular, we propose statistical methods to ensure that functional TCRs are not lost in pre-processing as well as methods to identify the clonotypes that are most likely to impact disease-relevant immune response. Taken together, successful completion of the project will help to ensure that maximal information is obtained from powerful TCR-seq experiments.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY Adult skeletal muscle possesses remarkable regenerative capacity. This ability is attributed to tissue- specific muscle stem cells (MuSCs), also called satellite cells. Upon activation, MuSCs are capable of exiting quiescence, proliferating, differentiating into muscle, and self-renewing. In addition to MuSCs, other cell types are known to support muscle development, growth, and regeneration. For instance, interstitial stromal cells that lie outside the basal lamina of muscle fibers are present from the earliest stages of muscle development and play critical roles in muscle patterning. However, muscle fibers and MuSCs derive from somites whereas interstitial/stromal cells derive from the lateral plate mesoderm. These lineages have been assumed to remain distinct throughout life. A handful of recent publications have challenged this paradigm and support the existence of a subset of interstitial stromal cells that have myogenic potential. We have previously reported that Hox11 genes are expressed in interstitial stromal cells that surround the muscle fibers of the zeugopod-attached muscles (radius/ulna, tibia/fibula) at embryonic stages and that loss of Hox11 function leads to disrupted muscle patterning. Recently published work from the Wellik laboratory reveals that Hox11 expression in the muscle interstitial stroma continues throughout life. Using a Hoxa11- CreERT2 allele generated in my laboratory to induce lineage labeling, we show that Hoxa11-expressing muscle interstitial cells contribute to muscle fibers beginning at postnatal stages. This contribution is MuSC- independent; MuSCs are not labeled using the Hoxa11-CreERT2 lineage reporter, and the lineage does not appear at any time post-induction in MuSCs. Use of Hoxa11-CreERT2 to induce nuclear lineage labeling (ROSA-LSL-H2BmCherry) supports interstitial cell nuclei contribution into muscle fibers (i.e. not just cytoplasmic contents). When cultured alone in myogenic media in vitro, Hoxa11 lineage-positive cells are unable to differentiate into myofibers, but when cultured with C2C12 or Pax7-lineage cells, Hoxa11-lineage cells are capable of contributing to existing myofibers, including in the presence of extracellular vesicle inhibitors. Our recent publication and new preliminary data supports the existence of a highly understudied set of Hox-expressing myoprogenitor cells. Further study of this novel subset of cells will fill gaps in our knowledge of muscle biology and could lead to new regenerative avenues for ameliorating the loss of muscle that occurs in dystrophinapathies. In this proposal, we will interrogate Hoxa11-lineage potential using multiple approaches in vivo, including in response to injury and induced hypertrophy (Aim 1). Using our collection of genetic tools, we will perform Hoxa11-CreERT2-mediated cell ablation studies, loss of Hox11 function studies and interrogate functional subsets and cellular mechanisms using various -omic technologies (Aim 2). We will define the in vitro cellular behavior and the ex vivo transplantation potential of Hoxa11 lineage-positive cells and compare them to other cells with myogenic capacity (Aim 3).

NIH Research Projects · FY 2025 · 2025-03

Squamous cell carcinoma (SCC) is responsible for ~10% of total cancer mortality worldwide. SCC prognosis is context-dependent and does not seem to be determined by driver gene somatic mutations, which are similar across different body sites and pathological grades. Our study of SCC arising in the rare genetic skin disease Recessive Dystrophic Epidermolysis Bullosa (RDEB) has identified genetic similarities between this deadly, tissue damage-driven cancer, and a related cancer arising in the oral cavity, termed head and neck SCC (HNSCC). Our unpublished research into HNSCC has demonstrated that this similarity extends beyond genetics and has identified the composition of the extracellular matrix (ECM) within the tumor microenvironment as a potential predictor of poor outcome. Our current proposal leverages the similarities between RDEB and certain sub-types of HNSCC to explore initiation and progression events that are likely driven by different environmental stimuli but which result in the same outcome; SCC with poor prognosis. In RDEB, ~90% of patients develop cutaneous SCC by age 55 and 5-year survival is close to 0%. SCC in the skin of RDEB patients arise within chronic wounds, an environment quite different to most head and neck cancers. Nevertheless, analysis of mutations in these tumors suggests that similar mechanisms are driving tumor initiation, and analysis of gene expression and ECM proteins suggests that similar mechanisms also drive tumor progression. We have developed a novel assay of mutation in cultured keratinocytes which will determine the extent of existing mutation in single cells isolated from peri-tumoral, normal-appearing tissue, a tissue region that is prone to cancer development (a phenomenon known as ‘field cancerization’). Using this approach, we will also determine the relationship between elements associated with risk factors in HNSCC, and mutagenesis driven by endogenous deaminases of the AID (activation-induced cytidine deaminase) and APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide) family, which have been shown to be active in all SCC genomes. To address the role of ECM in progression of SCC, we will utilize a novel assay of tissue fibrosis that recapitulates the continual collagen remodeling observed in SCC fibroblasts (in both RDEB and HNSCC) when compared with normal fibroblasts isolated from the same patient which do not exhibit such collagen remodeling. We will interrogate the role of thrombospondin-1 (TSP1) in driving tumor cell invasion through two separate but related mechanisms, activation of transforming growth factor-beta signaling and regulation of ECM secretion. In parallel, we will determine the timing of mutational processes resulting from tissue damage by assessing mutation acquisition in APOBEC transgenic animals. Importantly, these studies will also enable us to evaluate APOBEC inhibition as a potential preventative or treatment intervention for SCC in a pre-clinical setting. Together, our integrated in vitro and in vivo studies will provide the rationale and platform to develop clinically relevant strategies for improved SCC treatment and prevention.

NSF Awards · FY 2025 · 2025-03

As technology advances across aerospace, biomedical, and semiconductor fields, the demand for high-performance engineering materials continues to grow. Ceramics like sapphire and zirconia excel in extreme environments such as hypersonic flights, medical applications, and high-speed semiconductor devices. However, as these applications evolve, ceramic component designs become more complex and difficult to produce using conventional manufacturing methods such as grinding and polishing. Ultra-precision machining, which manipulates cutting tools at small length scales, has been developed to create complex geometries without costly post-processing. However, the tool-workpiece interactions and material removal mechanisms at this scale are not fully understood, limiting productivity. By combining precision cutting experiments with computer simulations, this research project aims to investigate the interactions between various deformation and fracture mechanisms and develop a predictive model to enhance machining efficiency and advance the manufacturing of cutting-edge technologies. Beyond immediate applications, the findings are anticipated to advance materials science by providing insights relevant to other high-performance materials. Project results will be shared through publications, conferences, and graduate courses. Moreover, this project will provide research opportunities for undergraduate students, fostering a broad talent pipeline in various science and engineering fields. Selecting optimal process parameters for ultra-precision machining of difficult-to-cut materials often relies on trial-and-error, leading to wasted resources and require extensive post-processing. Addressing these challenges requires predictive models based on a comprehensive understanding of material deformation in crystalline structures during machining. Current models primarily focus on single dominant deformation modes, which limits their ability to capture the complex interplay of slip, twinning, and fracture mechanisms involved in machining ceramics. This research aims to elucidate the interactions among various deformation and failure mechanisms during ultra-precision machining of single-crystal materials and their influence on machining performance. The study focuses on sapphire, examining how specific types of defects impact machining outcomes. Artificial defects will be introduced using focused ion-beam milling, enabling controlled investigations of individual deformation modes. To complement experimental efforts, atomistic simulations will be conducted to analyze the temporal evolution of deformations and the role of defects, such as dislocations and twinning, which are difficult to replicate experimentally. Insights gained will enhance existing material deformation models, moving beyond single-mode analyses. These improved models will support the development of machining strategies that optimize the machinability of advanced engineering ceramics, reducing costs and improving efficiency. 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 doctoral dissertation research improvement award supports research on how scientists structure and share genomic data, especially across disciplinary boundaries. The goal of this study is to identify the anticipated and unanticipated effects of genetic data practices to help scientists, decision-makers, and funders to better understand practices and structures of sharing genomic data. The findings of this research may contribute to data sharing practices, managing and controlling the downstream use of genetic data, as well as to improving data management and privacy. This study will trace the origins and circulation of specific data, data structures, and data-sharing practices in genomics, as well as the adaptation and consequences of those practices in social science genomics. The use of mixed methods will permit an understanding of the social and historical context of data sharing through the review of scientific and popular literature; semi-structured interviews; and participant observation. It will focus on online databases collecting genetic data, consortia for meta-analyzing these data, and cloud-based platforms for managing data analysis. The intellectual merit of the project will focus on the active role that data and data practices play in the negotiation of genomic objects, frameworks, and practices through data management. The study will contribute to the literature on studies of scientific field dynamics and critical studies of data centric science. 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.