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U.S. National Science Foundation

TheElectrochemical Systemsprogram is part of the Chemical Process Systems cluster, which also includes: 1) theCatalysisprogram; 2) theInterfacial Engineeringprogram; and 3) theProcess Systems, Reaction Engineering, and Molecular Thermodynamicsprogram. The goal of theElectrochemical Systemsprogram is to support fundamental engineering science research that will enable innovative processes involving electrochemistry or photochemistry for the sustainable production of electricity, fuels, chemicals, and other specialty and commodity products. Processes utilizing electrochemistry or photochemistry for sustainable energy and chemical production must be scalable, environmentally benign, reduce greenhouse gas production, and utilize renewable resources. Research projects that stress fundamental understanding of phenomena that directly impact key barriers to improved system or component-level performance (for example, energy efficiency, product yield, process intensification) are encouraged. Processes for energy storage should address fundamental research barriers for renewable electricity storage applications, for transport propulsion, or for other applications that could have impact towards climate change mitigation. For projects concerning energy storage materials, proposals should involve testable hypotheses that involve device or component performance characteristics that are tied to fundamental understanding of transport, kinetics, or thermodynamics. Advanced chemistries beyond lithium-ion are encouraged. Proposed research on processes utilizing electrochemistry or photochemistry should be inspired by the need for economic and impactful conversion processes. All proposal project descriptions should address how the proposed work, if successful, will improve process realization and economic feasibility and compare the proposed work against current state of the art. Highly integrated multidisciplinary projects are encouraged. When appropriate, collaborations with industrial technologists are encouraged through GOALI proposals. Collaborative projects with an integrated experimental and theoretical approach are also encouraged. Topics of interest include electrochemical energy storage and electrochemical production/conversion systems. Radically new battery systems can move the U.S. more rapidly toward a more sustainable transportation future and to greater renewable electricity production penetration. High-energy density and high-power density batteries suitable for transportation and renewable energy storage applications are of primary interest. Advanced systems involving metal anodes, solid-state electrolytes, nonaqueous systemsbeyond lithium, aqueous systems beyond lithium,and multivalent chemistries are encouraged. Research activities focused on commercially available systems such as lead-acid and nickel-metal hydride batteries or lithium-ion batteries for medical or consumer electronics applications will not be considered by this program. Novel electrochemical and photochemical systems and processes for the production of chemicals and high-value products are encouraged. Emphasis is placed on those systems that improve process intensification and process modularization with accompanying benefits in energy efficiency and environmental footprint. Additional fundamental science topics of interest to this program include the study of: advanced fuel cell systems or fuel cell components for transportation propulsion or grid energy storage applications; flow batteries for stationary energy storage applications including alternative redox chemistries (e.g., organic, inorganic, organometallic, macromolecular) and operating strategies (e.g., redox-mediation, suspensions); and photocatalytic or photoelectrochemical processes and devices for the splitting of water into hydrogen gas or for the reduction of carbon dioxide to liquid or gaseous fuels. Projects that largely focus on developing fundamental understanding of the catalytic reaction mechanisms and structure-function relationships may be more appropriate as submissions to the CBET Catalysis program (CBET 1401). Projects submitted to the Electrochemical Systems program are expected to develop fundamental, molecular-level understanding of the key chemical reaction and transport phenomena barriers to improved system-level performance. Innovative proposals outside of these specific interest areas may be considered. However, prior to submission, it is recommended that the Principal Investigator contact the program director to avoid the possibility of the proposal being returned without review. Referrals to other programs within NSF: Proposals that focus on electric-field driven separations such as dielectrophoresis should be directed to theInterfacial Engineeringprogram (CBET 1417). Proposals that focus on thermal management of energy storage devices and systems should be submitted to theThermal Transport Processesprogram (CBET 1406). Proposals that focus on improving device and system performance of primarily organic, inorganic, and hybrid photovoltaic (PV) technologies, including perovskites, may be more appropriate as submissions to the Electronics, Photonics, and Magnetic Devices program in Engineering's Division of Electrical, Communications, and Cyber Systems (ECCS 1517). PV materials proposals that focus on the material science may be considered in the Division of Materials Research of the Directorate for Mathematical and Physical Sciences. Proposals that focus on the generation of thermal energy by solar radiation should be directed to theThermal Transport Processesprogram (CBET 1406). INFORMATION COMMON TO MOST CBET PROGRAMS Proposals should address the novelty and/orpotentially transformative natureof the proposed work compared to previous work in the field. Also, it is important to address why the proposed work is important in terms of engineering science, as well as to also project the potential impact on society and/or industry of success in the research. The novelty or potentially transformative nature of the research should be included, as a minimum, in the Project Summary of each proposal. The duration of unsolicited proposal awards in CBET is generally up to three years. Single-investigator award budgets typically include support for one graduate student (or equivalent) and up to one month of principal investigator time per year(awards for multiple investigator projects are typically larger). Proposal budgets that are much larger than typical should be discussed with the Program Director prior to submission. Proposers can view budget amounts and other information from recent awards made by this program via the What Has Been Funded (Recent Awards Made Through This Program, with Abstracts) link towards the bottom of this page. Faculty Early Career Development(CAREER)program proposals are strongly encouraged. Award duration is five years.The submission deadline for Engineering CAREER proposals is in July every year. Learn more in theCAREER program description. Proposals for Conferences, Workshops, and Supplements: PIs are strongly encouraged to discuss their requests with the Program Director before submission of the proposal. Grants forRapid Response Research(RAPID)andEArly-concept Grants for Exploratory Research(EAGER)are also considered when appropriate. Please note that proposals of these types must be discussed with the program director before submission.Grant Opportunities for Academic Liaison with Industry (GOALI)proposals that integrate fundamental research with translational results and are consistent with the application areas of interest to each program are also encouraged. Please note that RAPID, EAGER, and GOALI proposals can be submitted anytime during the year. Details about RAPID, EAGER, and GOALI are available in theProposal & Award Policies & Procedures Guide(PAPPG), Part 1, Chapter II, Section E: Types of Proposals. COMPLIANCE: Proposals which are not compliant with theProposal & Award Policies & Procedures Guide (PAPPG)will be returned without review.

U.S. National Science Foundation

TheElectrochemical Systemsprogram is part of the Chemical Process Systems cluster, which also includes: 1) theCatalysisprogram; 2) theInterfacial Engineeringprogram; and 3) theProcess Systems, Reaction Engineering, and Molecular Thermodynamicsprogram. The goal of theElectrochemical Systemsprogram is to support fundamental engineering science research that will enable innovative processes involving electrochemistry or photochemistry for the sustainable production of electricity, fuels, chemicals, and other specialty and commodity products. Processes utilizing electrochemistry or photochemistry for sustainable energy and chemical production must be scalable, environmentally benign, reduce greenhouse gas production, and utilize renewable resources. Research projects that stress fundamental understanding of phenomena that directly impact key barriers to improved system or component-level performance (for example, energy efficiency, product yield, process intensification) are encouraged. Processes for energy storage should address fundamental research barriers for renewable electricity storage applications, for transport propulsion, or for other applications that could have impact towards climate change mitigation. For projects concerning energy storage materials, proposals should involve testable hypotheses that involve device or component performance characteristics that are tied to fundamental understanding of transport, kinetics, or thermodynamics. Advanced chemistries beyond lithium-ion are encouraged. Proposed research on processes utilizing electrochemistry or photochemistry should be inspired by the need for economic and impactful conversion processes. All proposal project descriptions should address how the proposed work, if successful, will improve process realization and economic feasibility and compare the proposed work against current state of the art. Highly integrated multidisciplinary projects are encouraged. When appropriate, collaborations with industrial technologists are encouraged through GOALI proposals. Collaborative projects with an integrated experimental and theoretical approach are also encouraged. Topics of interest include electrochemical energy storage and electrochemical production/conversion systems. Radically new battery systems can move the U.S. more rapidly toward a more sustainable transportation future and to greater renewable electricity production penetration. High-energy density and high-power density batteries suitable for transportation and renewable energy storage applications are of primary interest. Advanced systems involving metal anodes, solid-state electrolytes, nonaqueous systemsbeyond lithium, aqueous systems beyond lithium,and multivalent chemistries are encouraged. Research activities focused on commercially available systems such as lead-acid and nickel-metal hydride batteries or lithium-ion batteries for medical or consumer electronics applications will not be considered by this program. Novel electrochemical and photochemical systems and processes for the production of chemicals and high-value products are encouraged. Emphasis is placed on those systems that improve process intensification and process modularization with accompanying benefits in energy efficiency and environmental footprint. Additional fundamental science topics of interest to this program include the study of: <ul type="disc"> <li>advanced fuel cell systems or fuel cell components for transportation propulsion or grid energy storage applications;</li> <li>flow batteries for stationary energy storage applications including alternative redox chemistries (e.g., organic, inorganic, organometallic, macromolecular) and operating strategies (e.g., redox-mediation, suspensions); and</li> <li>photocatalytic or photoelectrochemical processes and devices for the splitting of water into hydrogen gas or for the reduction of carbon dioxide to liquid or gaseous fuels. Projects that largely focus on developing fundamental understanding of the catalytic reaction mechanisms and structure-function relationships may be more appropriate as submissions to the CBET Catalysis program (CBET 1401).</li> </ul> Projects submitted to the Electrochemical Systems program are expected to develop fundamental, molecular-level understanding of the key chemical reaction and transport phenomena barriers to improved system-level performance. Innovative proposals outside of these specific interest areas may be considered. However, prior to submission, it is recommended that the Principal Investigator contact the program director to avoid the possibility of the proposal being returned without review. Referrals to other programs within NSF: <ul type="disc"> <li>Proposals that focus on electric-field driven separations such as dielectrophoresis should be directed to theInterfacial Engineeringprogram (CBET 1417).</li> <li>Proposals that focus on thermal management of energy storage devices and systems should be submitted to theThermal Transport Processesprogram (CBET 1406).</li> <li>Proposals that focus on improving device and system performance of primarily organic, inorganic, and hybrid photovoltaic (PV) technologies, including perovskites, may be more appropriate as submissions to the Electronics, Photonics, and Magnetic Devices program in Engineering's Division of Electrical, Communications, and Cyber Systems (ECCS 1517). PV materials proposals that focus on the material science may be considered in the Division of Materials Research of the Directorate for Mathematical and Physical Sciences.</li> <li>Proposals that focus on the generation of thermal energy by solar radiation should be directed to theThermal Transport Processesprogram (CBET 1406).</li> </ul> INFORMATION COMMON TO MOST CBET PROGRAMS Proposals should address the novelty and/or<a href="http://www.nsf.gov/about/transformative_research/faq.jsp">potentially transformative nature</a>of the proposed work compared to previous work in the field. Also, it is important to address why the proposed work is important in terms of engineering science, as well as to also project the potential impact on society and/or industry of success in the research. The novelty or potentially transformative nature of the research should be included, as a minimum, in the Project Summary of each proposal. The duration of unsolicited proposal awards in CBET is generally up to three years. Single-investigator award budgets typically include support for one graduate student (or equivalent) and up to one month of principal investigator time per year(awards for multiple investigator projects are typically larger). Proposal budgets that are much larger than typical should be discussed with the Program Director prior to submission. Proposers can view budget amounts and other information from recent awards made by this program via the &ldquo;What Has Been Funded (Recent Awards Made Through This Program, with Abstracts)&rdquo; link towards the bottom of this page. Faculty Early Career Development(CAREER)program proposals are strongly encouraged. Award duration is five years.The submission deadline for Engineering CAREER proposals is in July every year. Learn more in the<a href="https://www.nsf.gov/career">CAREER program description</a>. Proposals for Conferences, Workshops, and Supplements: PIs are strongly encouraged to discuss their requests with the Program Director before submission of the proposal. Grants forRapid Response Research(RAPID)andEArly-concept Grants for Exploratory Research(EAGER)are also considered when appropriate. Please note that proposals of these types must be discussed with the program director before submission.Grant Opportunities for Academic Liaison with Industry (GOALI)proposals that integrate fundamental research with translational results and are consistent with the application areas of interest to each program are also encouraged. Please note that RAPID, EAGER, and GOALI proposals can be submitted anytime during the year. Details about RAPID, EAGER, and GOALI are available in theProposal &amp; Award Policies &amp; Procedures Guide(PAPPG), Part 1, Chapter II, Section E: Types of Proposals. COMPLIANCE: Proposals which are not compliant with the<a href="https://www.nsf.gov/publications/pub_summ.jsp?ods_key=pappg" target="_blank">Proposal &amp; Award Policies &amp; Procedures Guide (PAPPG)</a>will be returned without review.

Broad Foundation

Major funder of education reform, science research, and arts with $4B+ endowment.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Cognitive impairment persists even with highly effective antiretroviral therapy (ART) in people with HIV (PWH). Persistent neuroinflammation is one of many factors that contributes to ongoing cognitive impairment in virally suppressed (vs)PWH. However, there is a critical gap in understanding the underlying cause of neuroinflammation and, as a result, no available therapies to target it. Long-acting broadly neutralizing antibodies (bNAbs) are considered the next generation of therapy for PWH. Currently, there are 50+ trials that involve bNAbs. Despite this substantial effort, there are no funded NIH studies focusing on if bNAb therapy in combination with ART may reduce neuroinflammation and improve cognitive function. As the mechanism of action for bNAbs is the rapid neutralization of virus and clearance of infected cells via engagement of the immune system, a downstream effect of this therapy may be lower levels of inflammation, as is observed with other Ab therapies. We have evidence that HIV-specific antibodies (Ab) play a protective role in the CNS, and others have shown that bNAb therapy enhances host Ab immunity to HIV and simian immunodeficiency virus (SIV). Therefore, our central hypothesis is that bNAb therapy will reduce neuroinflammation in the CNS, by directly eliminating infected cells capable of trafficking to brain resulting in a smaller CNS reservoir, neutralizing virus within the CSF, and indirectly by reducing peripheral inflammation, resulting in improved cognition. To test our hypothesis, we will use the SIVmac251 rhesus macaque model of HIV and an SIV-specific bNAb (ITS103). The SIV-infected ART-suppressed NHP model will allow us to assess the effects of bNAbs on CNS inflammation, reservoir, and cognition. Additionally, this model will allow us to determine if bNAbs have a direct effect on the CNS or indirect effect through altering peripheral inflammation. AIM 1: Determine if bNAb therapy during ART initiation reduces neuroinflammation. To model ART-naïve PWH receiving bNAb therapy simultaneously with ART, we will treat SIV-infected macaques with ITS103 at the time of ART initiation. We will assess the effect of acute ITS103 therapy on 1) brain macrophage transcription, 2) CNS reservoir size, and 3) cognitive performance after 1 year of suppression compared to ART alone. AIM 2: Determine if bNAb therapy during chronic ART reduces neuroinflammation. To model vsPWH receiving bNAb therapy combined with ongoing ART, we will treat SIV-infected macaques with ITS103 after 36 weeks of ART suppression and assess the effect of chronic bNAb therapy on the same outcomes as in Aim 1. AIM 3: Determine if bNAbs have a direct or indirect effect on neuroinflammation. To determine if ITS103 plays a direct role in the CNS we will assess 1) ITS103 concentrations in the CSF, 2) viral decay rates in CSF, 3) central vs. peripheral inflammation and 4) plasma and CSF Ab neutralization capacity with and without bNAb therapy. Our in vivo study utilizing a native SIV and SIV-specific bNAb is highly innovative as it will be the first to study on the effects of bNAb therapy on neuroinflammation and evaluate if this is a viable treatment for PWH.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT Hirschsprung disease associated enterocolitis (HAEC) is the leading cause of death in children who lack enteric neurons in distal bowel, a birth defect called Hirschsprung disease. The etiology of HAEC is not well understood, but hypothesized disease mechanisms include altered gut microbes (“dysbiosis”), abnormal mucosal immune system and epithelial barrier defects. To date, there are no immune-targeted therapies to treat or prevent HAEC, but new treatments are needed. This proposal builds on the candidate’s preliminary data suggesting interleukin 22 (IL22) critically modulates HAEC risk and HAEC severity. The central hypothesis is that enteric nervous system (ENS) signaling induces IL22 release and facilitates IL22 epithelial responses to enhance mucosal immunity and strengthen epithelial barrier functions that prevent enterocolitis. The Piebald lethal (sl/sl) Hirschsprung disease mouse model of HAEC will be used, as survival of sl/sl mice is dramatically (> 3-fold) altered by diet (Tjaden et al, in BioRxiv and submitted) and IL22 mRNA is much higher in sl/sl fed a Protective diet that extends median survival (“late onset HAEC”). Aim 1 will define the cellular source(s) of IL22 from bowel regions of sl/sl model mice that develop early or late onset HAEC. In parallel, this aim tests the hypothesis that IL22 prevents HAEC, by using genetic and pharmacologic strategies to alter IL22 levels. Aim 2 will precisely define the role of IL22 on epithelial integrity, stem cell renewal and differentiation in organoids derived from sl/sl mice with early or late onset HAEC and from children with Hirschsprung disease with or without HAEC. Organoids facilitate studies of epithelial stem cell biology and IL22-epithelium interactions in the absence of microbes, neurons, or diffusible small molecules such as neurotransmitters. Collectively, these studies will determine cellular sources of IL22, the effect of ENS cells on IL22 secretion, the role of IL22 in enterocolitis, and the impact of Hirschsprung disease associated aganglionosis on epithelial cell biology. These studies build on the candidate’s training as a pediatric gastroenterologist, who has clinical exposure to the diagnosis and treatment of children with Hirschsprung disease and HAEC, as well as her basic science training in enteric nervous system biology. As the work proceeds, she will become an expert in mucosal immunology and epithelial biology with a focus on neuro-immune and neuro-epithelial interactions. The mentors, Dr. Robert Heuckeroth, and Dr. Kathryn Hamilton are experts in ENS biology and epithelial biology respectively. Both mentors have a strong commitment to mentorship and NIH funding track records. Experiments will be conducted at the Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, a collegial, collaborative and state-of-the art institution. The professional development and training plan will position the candidate as a successful pediatrician-scientist, who is focused on the prevention and treatment of Hirschsprung associated enterocolitis. These studies should determine if IL22-based therapies would likely be successful in HAEC, and if a human clinical trial is appropriate.

Velocity Dance Center

We propose a weekend of free community performances that are created by and for Black communities hosted in May 2025 at Kubota Garden in South Seattle. ?Elysium - Leviticus or Love and to walk amongst HUMANS: Book II?, is a site-responsive performance that leads audiences through a journey of death and revival to find themselves in a world where Black bodies are the blessed and dying to oneself is a rite of passage. Conceived and shaped by dani tirrell, choreographers Nia-Amina Minor, Quynn Johnson, Cyrah Ward, keyes wiley, and Majinn and performed by a cast of 20 local artists, this project is a celebration of the cultural practices of many overlapping identities held by the creators: the rituals of Black religious communities, Black LGBTQ+ nightlife practices like House and Club dance, and the power of gathering outdoors and sharing art together. The work will serve as a chance for Black communities to create and witness an arts event in an outdoor garden in their own neighborhood.

Gay City Health Project

The Emerge Arts Showcase offers emerging performance-based artists production and artistic mentorship and support alongside business and sustainability training. This framework will create a festival that is informed by, and seeks to address, artists' access to health and sustainability (as measured by social determinants of health) alongside artistic development and production. The anticipated project completion is August 31, 2022.

NIDA - National Institute on Drug Abuse

PROJECT ABSTRACT Emergency departments (EDs) face significant challenges managing mental health crises, often lacking specialized resources and leading to inappropriate placements and insufficient follow-up care. Emergency Psychiatric Assessment, Treatment, and Healing (EmPATH) units are designed to specially address these issues. However, a significant proportion of individuals experiencing mental health crises also have co-occurring substance use disorders, particularly opioid use disorder (OUD). Buprenorphine has been shown to reduce all-cause mortality. Furthermore, emergency department-initiated buprenorphine (EDIB) has demonstrated a doubling of 30-day treatment retention compared to referral alone. This significant success makes integrating EDIB into the EmPATH unit model a logical and potentially transformative step toward improved patient outcomes. However, adequately addressing workforce training needs is crucial for the successful implementation and sustained improvement of patient care. This project will develop and implement a training curriculum for EmPATH personnel focused on the acute management of OUD, emphasizing initiation of medication for opioid use disorder (MOUD) with buprenorphine. A phased approach will involve stakeholder input, protocol refinement, and rigorous evaluation. Phase 1 (R-61) will focus on curriculum development, incorporating input from an external advisory board, piloting the intervention in one EmPATH unit, and gathering qualitative feedback to refine the protocol. Phase 2 (R-33) will utilize a stepped-wedge design to: 1) assess the number of individuals identified with OUD while in EmPATH units (Primary Outcome) and the number of individuals administered buprenorphine and/or given a prescription for buprenorphine (Secondary Outcome); and 2) assess EmPATH staff satisfaction, burnout, confidence, knowledge, and stigma when working with patients with opioid use disorder prior to implementation and at 3, 6, 9, and 12 months post-implementation/training. This study aims to create a replicable and scalable model for integrating state-of-the-art OUD management into psychiatric emergency settings, improving patient outcomes and workforce preparedness. The collaboration with the South Carolina Hospital Association, Department of Mental Health, and DAODAS strengthens the project's impact and sustainability.

NIEHS - National Institute of Environmental Health Sciences

The ovary is a particularly important reproductive organ because it is essential for the production of oocytes and sex steroid hormones. Unfortunately, exposure to environmental endocrine disrupting chemicals (EDCs) can damage the ovary. EDC-induced ovarian damage leads to female reproductive dysfunction, which cannot be prevented or treated by eliminating EDC exposures. It is extremely important to understand the mechanisms by which EDCs damage the ovary so that we can develop strategies to prevent and/or treat EDC-induced reproductive toxicity. Towards this end, the overall goals of the proposed RIVER program are to: 1) unravel the intricate mechanisms underlying EDC-induced ovarian damage and female reproductive dysfunction, 2) decode the multigenerational effects of EDCs on ovarian function and female reproductive capacity, and 3) bridge the gap to human health by elucidating how EDC exposure is associated with ovarian function and reproductive aging in a prospective cohort of midlife women. To address these urgent clinical and public health needs, we will use single cell RNAseq to identify novel pathways of EDC-induced toxicity at the single cell level in the ovary as well as other female reproductive organs, spatial transcriptomics to map EDC-induced changes in gene activity while preserving spatial context, advanced 3-D ovarian follicle culture techniques to uncover the direct effects of EDCs on the ovary in a controlled environment, pioneering in vitro and in vivo experiments that include environmentally relevant individual EDCs and mixtures of EDCs, state-of-the-art LC-MS techniques to detect the concentrations of EDCs that reach the female reproductive organs and determine the ability of the ovary to detoxify or bioactive EDCs, high resolution LC-MS/MS techniques to conduct quantitative global and targeted proteomics, whole genome methylome analysis or reduced-representation bisulfite sequencing (RRBS) to identify the effects of EDCs on cell-type specific DNA methylation patterns in the ovary, spatial epigenome- transcriptome co-profiling to localize EDC-induced changes in specific cell types in the ovary and determine the interaction between EDC-induced methylation and gene expression changes, CRISPR-Cas 9 technology to correct EDC-induced DNA methylation errors in cells, LC-MS techniques at the forefront of the field to measure selected EDCs and biomarkers of reproductive function and aging in a prospective cohort of midlife women, and leading edge statistical models to assess associations between EDC mixtures and selected biomarkers/outcomes. The applicant is uniquely qualified to successfully lead the RIVER program. The applicant served as PI on 24 NIH-funded awards and her research produced over 325 peer-reviewed publications. The applicant has demonstrated a broad vision, conducted ground-breaking research, and made seminal contributions to the understanding of the impacts of EDCs on the ovary and female reproduction. The flexible and sustained RIVER support will help the applicant to continue pioneering and impactful research, mentoring, and leadership in environmental health sciences.

NIA - National Institute on Aging

ABSTRACT Numerous studies have demonstrated the "male-female health-survival paradox," where females exhibit a higher burden of age-associated disorders yet live longer than males. This paradox arises from a greater burden of chronic diseases in females, particularly those with a strong inflammatory or autoimmune component. A key factor contributing to inflammation-associated pathologies is endothelial cell (EC) dysfunction. This proposal aims to elucidate the molecular basis of sex-dependent differences in EC functions that may shape the outcomes of angiogenesis-driven diseases and aging in general. Our recent findings revealed that female ECs exhibit higher inflammation and reactive oxygen species (ROS) accumulation, with reduced angiogenic potential. These findings suggest biological sexual dimorphism in EC function, although the molecular mechanisms underlying these differences remain unclear. Toll-like receptors (TLRs), key innate proinflammatory mediators, recognize molecular patterns, including both pathogens and endogenous ligands generated by tissue damage and excessive oxidation. Analysis of multiple RNA sequencing datasets revealed that TLR2 and TLR4 pathways, specifically in ECs, are among the most significantly dysregulated in inflammation-associated pathologies and senescence. Moreover, gene expression profiling demonstrates that TLR2/4-related pathways are upregulated in female ECs compared to male ECs in vivo and in vitro. This upregulation seems to be driven by both increased TLR expression and higher levels of endogenous TLR ligands in females, collectively amplifying inflammatory responses. In vivo vascularization models showed a more substantial inflammatory component coupled with impaired angiogenesis and vascular remodeling in females. In EC-specific dual TLR2/4 knockout mice, eliminating these receptors abolished the pronounced differences between females and males in vascular models. This indicates that TLR2/4 pathways dominate sex-related differences in EC functions. While sex- specific differences in vascular diseases can arise from genetic, hormonal, or environmental factors, most research to date has focused on sex hormones. This project aims to shift the focus toward exploring the genetic components, particularly the role of endothelial TLR2 and TLR4 pathways in mediating these differences. Herein, we propose a new hypothesis: TLR2 and TLR4 on the endothelium are critical regulators of vascular responses, and augmented TLR2/4 activation contributes to increased vascular inflammation in females. We propose that endothelial TLR2/4-signaling is required for timely injury responses and tissue regeneration by regulating cytokine production and recruitment of inflammatory cells in females. We will utilize innovative transgenic mouse models, a pharmacological approach using phospholipid-based Reactive Carbonyl Scavengers (RCS) limiting the generation of TLR2 and TLR4, and state-of-the-art proteomics. Our studies will provide insights into the role of innate immune mechanisms in ECs and enhance our understanding of the genetic mechanisms responsible for sex differences in vascular pathologies, leading to more efficient therapeutics for both men and women.

NINDS - National Institute of Neurological Disorders and Stroke

Abstract The development of advanced biomaterials capable of electrical signal transmission is vital for regenerative medicine and bioelectronics, with injectable conductive nanogels showing significant promise. While naturally occurring, biocompatible extracellular conductive nanowires (ECNs) from anaerobic bacteria, such as the multi- heme cytochrome proteins, offer a compelling solution to the limitations of synthetic materials (e.g., solubility and biocompatibility), their widespread application is currently limited by challenges in their rational engineering and efficient production. Specifically, the recently discovered ECN protein family has not yet been integrated into recent novel AI protein design tools, and their complex in vivo assembly mechanisms remain poorly understood. This proposal will bridge these gaps by first identifying and engineering OmcE cytochrome nanowires that form large, ordered bundles. This involves comprehensive large-scale genomic and AlphaFold3-guided virtual screens to pinpoint novel OmcE homologs, followed by high-resolution cryo-EM characterization to elucidate their structural details and bulk conductivity measurements to confirm electrical properties. Subsequently, state- of-the-art AI tools will be employed to engineer novel OmcE variants exhibiting robust self-assembly into advanced conductive nanogels. Simultaneously, another major objective is to visualize the OmcE secretion system in situ to unravel its intricate assembly mechanism. We hypothesize that these nanowires assemble via a large outer membrane porin, analogous to the chaperone-usher pathway. Sub-tomogram averaging will be utilized to reconstruct the porin's structure at sub-nanometer resolution, providing critical molecular blueprints for the rational design of OmcE variants with enhanced self-assembly properties and enabling their efficient recombinant overexpression. Ultimately, this work will facilitate the precise engineering of "super" OmcE nanowires for conductive nanogels, offering transformative insights into their biosynthesis and establishing a foundation for a new generation of protein-based bioelectronic materials.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY Genome editing is rapidly transforming biology and medicine by enabling the precise modification of DNA sequences in vivo. The technologies used for genome editing have also provided a means to modulate the expression of a target gene by facilitating the recruitment of transcriptional effector domains to a target site. One such tool capable of recreating the native mechanisms of gene activation consists of catalytically inactive Cas9 (dCas9) fused with the histone acetyltransferase p300, which, by acetylating histones near a target site, can activate gene expression through a nearly physiological approach. Nonetheless, current dCas9-p300 systems are inefficient, unpredictable, and incompatible with adeno-associated virus (AAV) delivery, which hinders future applications of this technology. Here, we propose to integrate state-of-the-art techniques including protein engineering, machine learning, and viral-vector design to create an innovative toolkit of epigenome editors that can be used to activate gene expression in vivo. Aim 1 will leverage phylogenetic diversity and directed evolution in mammalian cells to identify p300 variants with enhance gene activation capabilities. In Aim 2, we will develop machine-learning models that integrate target-site sequence features and nucleosome architecture to predict actionable target sites for efficient acetylation and gene activation. And, in Aim 3, we will engineer split-intein and ultracompact epigenome editors that can be packaged within single or dual AAV vectors to enable in vivo gene activation. To accomplish these objectives, we have assembled a multidisciplinary team with collective expertise in epigenome editing (Dr. Perez-Pinera), computational biology (Dr. Song) and AAV gene delivery (Dr. Gaj). Our collaborative efforts will: (1) yield a toolkit of programmable, tunable, and deliverable gene-activation tools, (2) facilitate the discovery of fundamental principles for epigenome editor design, and (3) enable the development of therapeutic applications for multiple disorders including developmental and metabolic disorders. We anticipate that the innovative and interdisciplinary nature of this proposal will yield technologies that will broadly impact biotechnology and medicine.

NIAID - National Institute of Allergy and Infectious Diseases

New HIV infections continue and cannot be eradicated by current treatments due to a life-long reservoir of infected cells. This key obstacle to cure HIV consists of a reservoir of latently infected CD4+ T cells that persist despite long-term antiretroviral therapy (ART) and cause rebound of viremia if ART is interrupted. The R37 award AI157862 “Enhanced latency reversal and reservoir clearance in macaques” was funded in July 2021 with the overarching objective to obtain a deeper and broader understanding of the latency reversal induced by a SMAC mimetic (SMACm) and its potential to reduce persistent reservoirs using an innovative “kick and kill” approach. We have learned that treatment of SIV-infected, ART-suppressed macaques with the SMACm AZD5582, that activates the ncNF-kB signaling pathway, reactivates rebound competent latent reservoirs throughout the body. We also learned that the combination of AZD5582 and the BCL-2 inhibitor venetoclax reduced the intact SIV reservoir in peripheral blood and bone marrow but did not delay viral rebound after ART interruption. These findings highlight the intricate relationship between latency reversal, reservoir size, and viral rebound. We have three priority areas for the next phase of this R37 award that build on our body of work using venetoclax as well as broadly neutralizing antibodies (bNAbs), that have both antiviral and pro-immune effects. First, focus on reservoir establishment as an optimal time to intervene (rather than the maintenance phase). Second, focus on the antiviral immunity needed to complement venetoclax as a reservoir reducing intervention. And third, a deep dive into how the spatial landscape and immunovirologic features of infection are influenced by venetoclax. Our Central Hypothesis is that bNAb therapy will synergize with promotion of infected cell apoptosis through BCL-2 inhibition to limit reservoir formation. Using our expertise in conducting rigorous in vivo studies in nonhuman primates and immunovirologic multiomic analyses, we will test our hypothesis in three Specific Aims: 1) Define how venetoclax combined with bNAb therapy during early ART impacts decay of viremia, the intact reservoir, and the spatial landscape of infection; 2) Determine how venetoclax combined with bNAb therapy during early ART influences antiviral immune responses in a tissue-specific context; 3) Evaluate the virologic and immunologic impact of venetoclax and bNAb therapy given at start of ART versus at ART interruption. The experiments proposed will provide new evidence regarding the mechanisms of HIV/SIV reservoir establishment and how this process may be perturbed. Our experiments will evaluate safety and efficacy in a preclinical model. We hope that the results we generate will contribute to a cure for people living with HIV. RELEVANCE (See instructions): New HIV infections continue and cannot be eradicated by current treatments due to a life-long reservoir of infected cells. The goal of our research program is to identify targeted immunotherapies that reduce HIV reservoir formation when given early in infection with antiretroviral treatment. Our experiments will evaluate safety and efficacy in a preclinical model to inform approaches to cure HIV.

NIA - National Institute on Aging

Alzheimer’s disease and related dementias (ADRD) are a growing public health burden and understanding modifiable ADRD causes is a national priority. Many classes of environmental chemicals, such as pesticides and per- and polyfluoroalkyl substances (PFASs) contain known neurotoxicants and are thus likely to contribute to ADRD risk, but we lack prospective data with appropriate temporality (exposures measured years before cognitive outcomes) in large and representative populations. Leveraging stored biospecimens from one of the largest, longitudinal, population-based United States cohorts, the Health and Retirement Study (HRS), we will generate a publicly available, prospective, environmental chemical resource, with exposure measures many years before the onset of ADRD or preclinical impairment. HRS participants are ages 50 and older and they have extensive existing biannual cognitive measures and ADRD fluid biomarker measures. Specifically, in Aim 1, we will perform new state-of-the-art non-targeted analysis in serum to measure chemical levels, including PFAS and pesticides, and test for association with cognitive function and decline, ADRD biomarker levels, and ADRD incidence. People are simultaneously exposed to pesticides, PFAS, and other chemicals in the neighborhoods where they live, work, play, and socialize. Social exposures, at the individual- and neighborhood-level contribute to stress and ADRD risk. Chemical and social exposure levels differ across US neighborhoods, with variation by geography and socioeconomic status. Therefore, in Aim 2, we will integrate mixtures of chemical and social exposures into the “exposome”, representing the totality of a person’s environment, when examining complex environmental contributors to ADRD. Additional evidence linking exposures and ADRD can be provided by intermediate molecular markers. These molecular intermediates may serve: 1) as biomarkers of exposure useful when direct exposure measures are not possible, 2) as mediators mechanistically linking exposure and ADRD, and 3) as connecting networks informing on overlapping pathways to deepen chemical and ADRD response understanding. In Aim 3, we will leverage existing measures of molecular intermediates, including DNA methylation, RNA expression, and immune cell profiles, with new measures of endogenous metabolomics and lipidomics, to assess molecular markers as exposure biomarkers or mediators to link exposures with incident cognitive status. Together, this project will identify individual chemicals, mixtures of chemicals, and their pathways that contribute to ADRD risk in a nationally representative sample, which will support ADRD prevention and intervention. Given widespread exposure levels to these environmental chemicals in the US, even modest associations with ADRD could represent a substantial number of preventable cases through individual- and population-level actions.

NIH

The overall goal of the proposed CDA-2 is for Dr. Fischer to obtain advanced training in various methods of psychiatric genomics (e.g., statistical genetics, epigenetics, transcriptomics) that he can use to supplement and strengthen his existing program of research, which examines environmental risk and protective factors for various psychiatric disorders and clinical problems, including suicidal thoughts and behaviors (STBs). This training will enable Dr. Fischer to systematically and comprehensively examine the biopsychosocial etiology of STBs, which will ultimately help to inform the treatment and prevention of STBs in U.S. Veterans. To accomplish this goal, Dr. Fischer will investigate how environmental (i.e., psychosocial) risk and protective factors interact with polygenic liability for STBs, along with how epigenetic processes are associated with STB phenotypes (i.e., suicidal ideation and suicide attempts). This project is innovative in that it will be one of the first to examine whether psychosocial risk and protective factors potentiate or mitigate polygenic risk for suicide in U.S. Veterans. It will also be, by far, the largest study to date on the epigenomics of STBs and the first to derive methylation risk scores for STBs. The proposed study will leverage cutting-edge statistical methods and state-of-the-art bioinformatics to provide novel insights into the complex etiology of STBs that will ultimately help inform efforts to reduce Veteran death by suicide. This CDA-2 grant will build on Dr. Fischer’s strong scientific background in Veteran mental health, psychiatric epidemiology, and environmental risk and protective factors, along with his ongoing experiences as a clinical psychologist, to provide him with crucial new knowledge and skills, which will support the generation of novel, multidisciplinary research. Through the proposed CDA-2, Dr. Fischer will develop the ability to: 1) generate polygenic risk scores; 2) conduct gene enrichment analyses and transcriptome-wide association studies (TWAS); 3) perform drug repurposing analyses; 4) conduct epigenome-wide association studies (EWAS); 5) derive methylation risk scores; and 6) leverage advanced machine learning approaches to evaluate multi-level predictive models. Dr. Fischer’s multidisciplinary mentorship team is composed of world-leading experts working within the VA Connecticut Healthcare System and Yale University. The high-quality research and collaborative environment present at these institutions will facilitate Dr. Fischer’s transition into an independent VA researcher and equip him with the tools needed to produce impactful, innovative research that advances the U.S. Department of Veterans Affairs top research and clinical goals: suicide prevention.

NIEHS - National Institute of Environmental Health Sciences

ABSTRACT Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants known for their widespread use and adverse effects on human health (e.g., metabolic disease, cancer). Early-life exposure to PFAS is of particular concern as developmental periods are a critical window of vulnerability during which disruptions to the gut microbiota and host metabolism can have long-lasting consequences. Infants and young children are exposed to PFAS through breast milk, formula, and contaminated food or water. Despite the recognition that many environmental pollutants influence the gut microbiota, there is a lack of research assessing PFAS-induced microbiome toxicity using quantifiable and biologically meaningful endpoints. Further, given the essential connection between the host and microbiome, there is a critical need to study the impact of PFAS on the physiology and function of gut microbes and the resulting effects on host health. The proposed studies will address these gaps by elucidating the mechanisms by which PFAS influences host-microbiome interactions. The central hypothesis of this grant is that gut microbes modify PFAS toxicokinetics and mediate PFAS- associated health outcomes via the disruption of host-microbe homeostasis. Herein we present a paradigm- shifting view of bacterial-mediated mechanisms of PFAS toxicity. Two specific aims will test this hypothesis: Specific Aim 1 will evaluate the effects of PFAS on diverse gut microbes to understand microbial toxicity, bioaccumulation, and adaptation in microbial species key to health. For Specific Aim 2, mouse models will be used to determine how early-life PFAS exposure disrupts the host-gut microbiome axis leading to metabolic disorders in adulthood. Our interdisciplinary team combines expertise in perfluorinated chemical toxicology, microbiology, metabolomics, and biostatistics. To comprehensively study how PFAS exposure is linked to detrimental health outcomes, our studies use state-of-the-art technologies (e.g., metagenomics, metabolomics) to explore microbial toxicity and the broader effects of environmental chemicals on gut microbiome and its community structure and function. Results from the proposed studies will provide new and impactful data that will provide for more personalized risk assessment frameworks and support the development of microbiome- centered therapeutic strategies to mitigate the health impacts of PFAS.

Sand Point Arts and Cultural Exchange

Sand Point Arts and Cultural Exchange will purchase and install equipment that will allow the KMGP 101.1 radio station to provide free community programming. The programming and production equipment will be installed within Warren G. Magnuson Park at 7400 Sand Point Way NE and the station's antenna will be installed at the University of Washington's McMahon Hall located at 4249 Whitman Court. Planning and installation activities will occur during the summer of 2017.

NIAID - National Institute of Allergy and Infectious Diseases

Abstract The presence of a reservoir of cells harboring integrated, replication-competent virus that persists under long-term, fully suppressive antiretroviral therapy (ART) and the inability of the host immune responses to control the initial events of viral replication that follow ART interruption are critical barriers to curing HIV infection. Thus, novel therapeutic strategies to remove these barriers are critically needed. The overarching hypotheses of ERASE HIV are: (i) decreased and/or dysfunctional CD8+ T and NK cell antiviral functions, combined with the recently-described CD8+ T-cell-mediated transcriptional silencing of HIV, favour HIV persistence under ART and prevent the control of viremia if ART is stopped; and (ii) novel approaches to elicit effective CD8+ T-cell, NK cell, and antibody-dependent cellular cytotoxicity (ADCC) functions while inhibiting the CD8+ T-cell-mediated virus silencing will promote remission and/or eradication of HIV. The overarching goal of ERASE HIV is to identify novel mechanisms of HIV persistence and to test them in the most relevant pre-clinical animal models through mechanistically-oriented, community-supported therapeutic strategies that can be ultimately translated to cure HIV infection in humans. ERASE HIV includes three highly integrated Research Foci (RFs). RF1 is aimed at identifying the molecular and cellular mechanisms underlying the two distinct antiviral activities of CD8+ T-cells: the MHC-restricted, Ag-specific response that directly eliminates virus-infected cells, and the non-MHC restricted, non-cytolytic silencing of HIV transcription. As such, RF1 will provide the conceptual basis for the interventions tested in RF2 and RF3. RF2 will use animal models of ART-treated HIV infection to (i) restore CD8+T and NK cell function with an α-IL-10 and IL-15 superagonist (N-803) strategy; (ii) target rebounding virus by using a CD4-mimetic compound (CD4mc) to enhance antibody recognition of cells expressing HIV Env and their elimination via ADCC; and (iii) determine if improving CD8 T and NK cell function via α-IL-10 and N-803 synergizes with CD4mc to clear infected cells. RF3 will determine if suppression of the latency-promoting activity of CD8+ T-cells, coupled with N-803 and interventions to promote apoptosis (Bcl-2 inhibitors) or immune-mediated removal (CD4mc) of cells that have reactivated virus, will reduce the reservoir size. In all, we will exploit the synergy between the mechanistic data generated in RF1 and the in vivo interventions in RF2 and RF3 to validate a strategy that targets both HIV persistence during ART and HIV recrudescence after ART interruption. ERASE HIV is supported by experts in HIV advancements (SisterLove); recognition and killing of HIV Env-expressing cells (Finzi/Sodroski); T and NK cell biology (Sekaly/Ribeiro/Deleage/Parsons); reservoir assays and latency models (Kulpa/Jones/Litchterfeld/Howell); pre-clinical animal studies (Paiardini/Silvestri/Garcia/Saez-Cirion/Keele/Kumar); mathematical modelling (Davenport); and therapeutics development (Merck and ImmunityBio) for HIV cure. We believe that the proposed mechanistically-oriented pre-clinical work will inform strategies that can be translated in clinical trials to achieve prolonged viral remission in PWH.

Erie Community Foundation

Erie Community Foundation ($300M in assets) supports nonprofits in PA through grants focused on education, community development, health, arts. Awards range from $2,000 to $100,000.

Eritrean Association of Greater Seattle

The Eritrean Association of Greater Seattle will organize an Eritrean Independence Day Celebration at Seward Park on May 25, 2019. The family-friendly event will feature Eritrean singers and musicians, local Eritrean children and youth performing traditional dances, poetry readings, drama, and a showcase of visual arts. There will be a soccer tournament the preceding weekend, May 18-19. Several thousand people are expected to attend the festival and tournament.

Esmee Fairbairn Foundation

45M+ GBP/year across arts, children & young people, environment, and food. One of UK's largest independent funders.

NCI - National Cancer Institute

Project Summary The postnatal development of the mammary gland is dependent on a multitude of cellular programs that are orchestrated by steroid and peptide hormones as well as locally produced cytokines. Two Janus kinases, JAK1 and JAK2, are obligatory intracellular signaling mediators of many peptide hormones and cytokines that have essential functions for the growth, differentiation, and survival of the mammary epithelium. Previous work from several laboratories including our own has established that JAK1 and JAK2 have non-redundant functions for the activation of specific Signal Transducers and Activators of Transcription (STATs) in normal and neoplastic epithelial cells. Important roles of these canonical JAK/STAT signaling cascades during mammogenesis are generally thought to be limited to the differentiation and remodeling of alveolar cells during the gestation cycle. In contrast to this notion, our team has discovered that JAK1 and JAK2 synergistically control the postnatal development of the mammary epithelial ductal tree. We uncovered that STAT proteins are activated in a compensatory manner in ductal epithelial cells, but the collective results from several genetically engineered mouse models revealed that the cooperative functions of JAK1 and JAK2 are not facilitated by their downstream STATs. Unlike in JAK1/2 mammary-specific double knockout mice, the growth and survival of mammary epithelial cells do not require the expression and/or activation of the seven known mammalian STAT proteins. We, therefore, propose that the biologically relevant functions of JAKs during postnatal mammary gland development are facilitated by noncanonical molecular signaling mechanisms of JAK1 and JAK2. Additional preliminary findings also raise the issue of whether the significant biological roles of JAKs are solely dependent on the functionality of their tyrosine kinase domains. To interrogate the noncanonical functions of JAK signaling, we will first establish whether the JAK1/2-dependent signaling mechanisms that govern the development of a mammary gland are dependent on the kinase and/or scaffold functions of JAKs (aim 1). Next, we will investigate the activation of JAK substrates that are currently known and use state-of-the-art genomic and proteomic approaches to identify novel targets and pathways that rely on JAK1 and JAK2 without the expression and activation of STATs (aim 2). Since JAK1/2 kinase inhibitors were clinically ineffective in treating advanced breast cancers, we will investigate the significance of noncanonical JAK signaling in mammary tumor cells and the effects of pharmacologically targeting JAK1/2 for degradation in human-relevant breast cancer models (aim 3). The collective outcomes of this project are expected to provide substantial new insights into the central roles of peptide hormone and cytokine signaling in mammary gland development. The anticipated results from the three aims will elucidate novel molecular mechanisms by which Janus kinases signal within normal and neoplastic epithelial cells beyond the activation of STAT proteins and establish whether pharmacologically targeting JAK1/2 for degradation is a suitable strategy for the treatment of breast cancer.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY A functional cure for HIV that maintains lifelong suppression of viremia without antiretroviral therapy (ART) remains an urgent unmet need. Broadly neutralizing antibodies (bnAbs) can control HIV, but vaccines have failed to induce them because they require unusual structural features that are not readily generated by natural B cell maturation. Genome engineering now allows mature bnAb genes to be inserted into the immunoglobulin heavy chain (IgH) locus of primary B cells, where they function as antigen receptors capable of undergoing germinal center maturation and forming memory responses. In mice, IgH-reprogrammed B cells generate durable bnAb titers near therapeutic levels after vaccination. However, the in vivo behavior of genome-engineered human B cells has not been tested due to the lack of an appropriate model. The recently developed Truly Human Xenograft (THX) mouse supports robust antigen-dependent human B cell responses and thus provides a unique opportunity to establish a preclinical platform for engineered B cell therapies. In Specific Aim 1, we will determine whether IgH-reprogrammed human B cells can participate in germinal center reactions and generate memory and long-lived plasma cells following vaccination in THX mice. In Specific Aim 2, we will establish an HIV infection and treatment model in THX mice, adapting mucosal challenge, ART suppression, and analytical treatment interruption protocols to evaluate viral rebound and reservoir establishment. Completion of these aims will demonstrate feasibility of eliciting vaccine-responsive bnAb memory responses from genome-engineered human B cells in vivo, while also establishing the THX mouse as a physiologically relevant platform for HIV infection and treatment studies. Together, this work will provide a critical foundation for advancing engineered B cell vaccines as a potential functional cure for HIV.

NIMH - National Institute of Mental Health

ABSTRACT The long term goals of these studies are to identify motor imitation as a biomarker of autism spectrum disorder (ASD) to both deepen understanding of brain and behavioral mechanisms for comorbid conditions and improve diagnosis with a cost-effective, objective, and reliable assessment method we developed. Although ASD is defined by core deficits in social-communicative functioning and restricted interests and repetitive behaviors, an ASD diagnosis is often accompanied by clear impairments in motor control and learning that present early and persist through childhood and into adulthood. Prominent among these ASD-associated motor impairments is difficulty imitating others’ actions (i.e., motor imitation). Imitation is crucial to social-communicative development, and impaired imitation has long been recognized as a likely contributor to the core difficulties in ASD. Crucially, while movement difficulties are associated with several developmental conditions that commonly co-occur with ASD, including attention deficit hyperactivity disorder (ADHD) and intellectual disability (ID), current literature suggests that deficits in motor imitation may distinguish these overlapping conditions and capture variation relevant to underlying biology of ASD. Efforts to establish imitation as a biomarker of ASD have been hampered by a lack of objective, reliable assessment, with studies thus far applying labor intensive methods that require subjective assessment by highly trained researchers/clinicians. Our team has pioneered the development of an automated Computerized Assessment of Motor Imitation (CAMI) to quantify ASD-associated imitation deficits with better diagnostic discrimination ability than traditional methods. A remaining challenge in developing motor imitation as a phenotypic biomarker is to establish the specific neural mechanisms contributing to imitation deficits. Previous fMRI studies on motor imitation in ASD have shown mixed results, possibly due to the significant limitations in assessing naturalistic motor imitation in the fMRI scanning environment, where there are substantial constraints on motion. To address this challenge, our team develops high-density diffuse optical tomography (HD-DOT) that enables fMRI-comparable image quality in an open setting. Herein, we propose to establish the specificity of motor imitation impairments (Aim 1) as well as the brain mechanisms underlying such impairments (Aim 2) of ASD relative to ADHD and ID. Our proposed study, by integrating state-of-the-art methods for quantitative, objective motor imitation assessment and concurrent identification of ASD-specific underlying neural correlates, has substantial potential to profoundly improve predictive diagnostic utility over current subjective clinical assessments and thereby aid public health efforts to identify and support affected children. ASD-specific neurobehavioral biomarkers identified through our proposed CAMI and HD-DOT methods may advance clinical subtyping of ASD and opportunities for individualized treatment, refine monitoring response to intervention, and inform underlying neurobiological mechanisms.