Grants

NIAID - National Institute of Allergy and Infectious Diseases

Research Summary Invasive aspergillosis (IA), primarily caused by Aspergillus fumigatus, is a life-threatening infection that predominantly affects immunocompromised individuals. Despite advancements in antifungal treatments, IA is associated with high mortality rates; for instance, among solid organ transplant recipients, mortality rates range from 65% to 92%, with IA contributing to approximately 9.3%–16.9% of all deaths within the first-year post- transplantation. A. fumigatus is also an important cause of fungal keratitis (FK), a site-threatening corneal infection that occurs in otherwise healthy patients that experience corneal trauma. As with IA, visual outcomes associated with FK are also poor, with 70% of all patients experiencing reduced or complete loss of vision in the affected eye. These statistics underscore the urgent need for novel therapeutic strategies for both pulmonary and corneal A. fumigatus infection. Pantothenate kinases are essential enzymes involved in the biosynthesis of coenzyme A (CoA and Acetyl-CoA (AcCoA) (The PCA pathway). Our studies have demonstrated that inhibition of PanK activity and the PCA pathway not only impedes fungal growth but also disrupts vacuolar function, compromising the pathogen's ability to detoxify antifungal agents. This dual mechanism suggests that PanK inhibitors can serve both as standalone drugs and as potentiators of existing antifungal drugs. We previously screened a library of 256,000 compounds against A. fumigatus AfPanK and identified pyrimidone triazoles (PTZs) as potent and selective inhibitors of this essential enzyme. Using structure-activity relationship (SAR) studies we designed and synthesized a focused library of 113 PTZ analogs. The goal of this R21/R33 proposal is to evaluate the biochemical activity, pharmacological properties and in vitro and in vivo efficacy of these compounds and identify potent dual-activity PTZ molecules to develop as novel antifungal agents against A. fumigatus infection. In the R21 phase, we will screen this focused library of PTZ analogs against purified AfPanK and a CDC collection of drug-sensitive and -resistant A. fumigatus clinical isolates. Potent candidate inhibitors will be further evaluated for their ability to augment the antifungal activity of clinically-approved anti-A. fumigatus agents including azoles, liposomal amphotericin B, and echinocandins. Transition milestones include the identification of lead compounds with defined inhibitory profiles and synergistic effects with existing drugs. In the R33 phase, we will conduct advanced in vitro efficacy and safety studies on the lead compounds, perform detailed pharmacological analyses, and assess the in vivo efficacy of lead compounds alone and in combination with approved antifungals using animal models of IA and FK A. fumigatus infections to validate their therapeutic potential. Successful completion of this project will yield novel AfPanK inhibitors that alone or when combined with approved antifungal drugs, can kill both sensitive and resistant A. fumigatus isolates. This therapeutic approach aims to reduce toxicity and improve treatment outcomes, potentially revolutionizing antifungal therapy.

DOT

Duck Pond Road intersection improvement

VINCENT D PISANI DBA BEHAVIOR CONSULTANTS INTERNATIONAL

Healthcare Services

NYC Department of Cultural Affairs

DUMBO District Management Association, Inc.

Duncan Area Economic Development Foundation

Duncan Area Economic Development Foundation is an active grantmaking foundation based in Duncan, OK. Focus: community development. Contact the foundation directly for current funding opportunities.

Saint Paul PHA

Preservation

Saint Paul PHA

New construction

City of Richmond

First Nails

Dupage Community Foundation

Dupage Community Foundation is an active grantmaking foundation based in Downers Grove, IL. Focus: philanthropy. Contact the foundation directly for current funding opportunities.

NCI - National Cancer Institute

PROJECT SUMMARY/ABSTRACT Melanoma is the most lethal type of skin cancer. About 50% of patients with metastatic melanoma have a meaningful response to treatment with immunotherapy, of which some develop a durable response. Many patients with the best response to immunotherapy develop immunotherapy-induced melanoma-associated vitiligo (MAV), an autoimmune cutaneous side effect. Previous mouse work has revealed that tissue-resident memory T cells (TRM) in vitiligo-skin with specificity for melanoma antigens were required for long-lived protection against melanoma. By examining human specimens, our recent studies revealed that long-term melanoma survivors with MAV maintain tissue-resident memory T cells (TRM) which were long-lived and functional. TRM have recently been recognized by our group and others as critical participants in anti-tumor immune responses. We identified a TRM subset characterized by high interferon gamma expression (TRM-IFNG) that is highly prognostic for improved survival in melanoma patients. Strikingly, TRM-IFNG cells had precursors in the patient’s primary melanoma up to 6 years prior, showing durability of the patient’s natural immune memory response. While there have been many studies focusing on metastatic melanoma, there is a gap of knowledge in understanding how the immune response to primary melanoma affects the recurrence and overall survival of melanoma patients. The goal of this proposal is to investigate the TRM response at the time of primary melanoma diagnosis and test its requirement for immunotherapy response. Our hypothesis is TRM-IFNG cells are established at the time of primary melanoma and are recalled and expanded in order to mediate responses to immunotherapy (IT). We will test this using melanoma mouse models as well as prospectively collected patient specimens to determine how TRM-IFNG formed in skin and tumor at the time of initial melanoma occurrence mediate responses to immunotherapy in the metastatic setting. In a preclinical model, we will utilize a topical immunotherapy to increase the TRM repertoire in primary and metastatic melanomas in order to set the stage for a future clinical trial aimed at treating primary melanoma as a way of inducing durable cancer-fighting TRM cells in patients. Successful completion of this proposal will advance our knowledge of the contribution of early disease TRM establishment to long-lived memory. Our long-term goal is to advance the understanding of durable immunity to cancer and provide new avenues for immunotherapy development and improved patient survival.

NIH

Significance to VA: Chronic low back pain (cLBP) is a highly prevalent condition for veterans. In addition to chronic pain, cLBP leads to significant amounts of disability, reduced health-related quality of life (QOL), and increased health care utilization. Our previous results and other studies of yoga for Veterans with cLBP show that yoga participants had reduced pain and disability at follow-up assessments at 6-month follow-up. There is also some evidence indicating that self-care treatments like yoga, especially those provided in group format, may be less expensive and may reduce health care costs, conserving limited resources for other conditions and services. Since persons with cLBP usually live with this chronic condition for the rest of their lives, understanding and facilitating long-term yoga practice for VA patients is an important step for the provision of high-quality VA healthcare. Innovation and Impact: If funded, this will be the first study to examine a durability intervention for promoting long-term yoga practice. It uses text messaging for both behavioral reminders, and for ecological momentary assessment of the durability outcome. The study tracks 18 months of follow-up data. Specific Aims: The primary aims of the proposed project are to examine the effectiveness of a coaching intervention plus text reminders for promoting long-term maintenance of yoga practice and function among Veterans with cLBP. We will also examine intervention costs and subsequent health care costs. Methodology: We will recruit and randomize 176 Veterans with cLBP to either standard yoga or the durability-enhanced yoga intervention. Participants will complete health outcome assessments at baseline, 3 months, 6 months, 12 months, and 18 months. The standard yoga intervention includes weekly in-person yoga sessions for 12 weeks. The enhanced yoga arm will receive weekly behavioral coaching sessions from weeks 10-15 and will receive ongoing text reminders. The co-primary outcomes will be the mean days and minutes per week of yoga practice and the mean change in back pain-related disability at 12 months. We will measure yoga practice and other health outcomes including pain severity, QOL, and fatigue through 18 months. We will measure attendance and home practice. We will monitor and assess adverse events and instructor fidelity. Path to Translation/Implementation: If the durability intervention can increase long-term yoga practice and associated health benefits, this will provide very strong evidence for wider implementation of yoga as a specific treatment for chronic low back pain.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Intramuscular SARS-CoV-2 mRNA-LNP do not reliably nor durably elicit respiratory mucosal IgA. Moreover, vaccinated individuals who become infected are more durably protected and this is thought to be mediated by respiratory mucosal IgA. Currently, there are no mucosal respiratory vaccines for human use. We identified a mucosal booster vaccine admixed with a mast cell agonist adjuvant, mastoparan-7, and a toll-like receptor 9 agonist adjuvant, CpG, that elicits durable mucosal IgA. Importantly, mice intranasally boosted with a multivalent nanoparticle vaccine adjuvanted with mastoparan-7 and CpG are protected from bat SARS-like virus challenge. We propose to study the mechanism of mast cell and antigen-presenting cell signaling modulated by this novel mucosal adjuvant combination. We will pursue our central objective which is to understand how mucosal IgA is elicited and maintained following respiratory mucosal vaccination with our exciting universal vaccines to ultimately achieve durable and broadly protective immunity against zoonotic coronaviruses. To achieve this objective, we will complete these aims: Aim 1: Test the hypothesis that mast cells and antigen-presenting cells elicit specific cytokines and chemokines that modulate durable IgA. We propose to study the impact of intranasal boost dose and interval on IgA kinetics and durability. We will also define if the mastoparan-7 and CpG adjuvant combination requires mast cell and antigen presenting cells that signal through CpG via the TLR-9 pathway. We will then define gene expression profiles from respiratory tract mast cells and antigen presenting cells that are activated by mastoparan-7 and CpG and modulate durable mucosal IgA responses. Aim 2: Test the hypothesis that M7/CpG nanoparticle vaccine elicits durable IgA secreting cells and IgA memory B cells in the respiratory tract using lineage-tracing, fluorescent reporter mice pre- immune with common-cold CoV. We will determine how intranasal boosting modulates IgA-secreting plasma cells and IgA memory B cells that home back to the respiratory mucosa in SARS-CoV-2 immune mice and in mice immune against common-cold coronaviruses. We will use cre-lox inducible, IgA-secreting cell and IgA memory B cell fluorescent reporter mice to define how intranasal boosting modulates mucosal IgA immunity. We will also test adjuvant and intranasal safety using a human lymph node organoid model from upper- respiratory tract draining lymph tissue from humans. Aim 3: Test the hypothesis that durable mucosal IgA can protect against transmissible SARS-CoV-2 variants in hamster transmission models and protect against SARS-related coronaviruses. We will determine if the mastoparan-7 and CpG adjuvanted nanoparticle intranasal booster reduces transmission of SARS-CoV-2 variants in hamster models. We will also use IgA knockout mice to determine if IgA is required for protection against SARS-like viruses.

Durango Education Foundation

Durango Education Foundation is an active grantmaking foundation based in Durango, CO. Focus: education. Contact the foundation directly for current funding opportunities.

NSF

The general picture that planets form in a protoplanetary disk, the spinning disk of gas and dust that surround young stars, is well established. How exactly planet formation proceeds from disks to planetary systems remains less clear due to uncertain properties of gas dynamics and the coupling of solid particles to the gas. Through computer simulations of the process of planet formation in rings, this research team will make predictions for the occurrence of planets that are currently too small to be detected but will soon be measured. The project will leverage social media to communicate scientific topics to a large, public audience. The new Department of Astronomy & Astrophysics at UC San Diego administers an Instagram account, which this project’s personnel manages and regularly updates with reels (short videos) showcasing astrophysical concepts and cutting-edge research by Department members. Graduate students in the Department will sharpen their scientific communication skills useful in academia and beyond in a formal professional development course to be developed as part of this project, including a module to produce the Instagram reels. The uncertain parameters of macro- and micro-physics in modern theories of planet formation severely limits their predictive power. This project breaks the measurement degeneracy between the Stokes number St and gaseous effective viscosity alpha, parameters that characterize the initial conditions of planet formation, by combining a large sample of ringed disks with the dust equation of motion. Direct simulations of the formation and mass growth of clumps inside dust rings will be pursued with the GIZMO hydrodynamic code, including self-gravity and sampling the observationally-inferred range of St and alpha. Prediction for the planet mass function at orbital distances of several to tens of astronomical units will be derived from the results of the GIZMO simulations convolved over the Galactic distribution of host star, disk, and environmental properties. Altogether, the proposed research has the potential to significantly advance our understanding of the critical microphysical properties of the protoplanetary disks and to make a direct link between these initial conditions and the properties of the observable exoplanets, producing specific and timely theoretical predictions of a distance-dependent planetary mass function that can be tested with upcoming observations. 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

Galaxies are made of many different components, not only stars, and some of their parts are difficult to detect because they do not emit visible light. Dust is one of these dark, yet ubiquitous, components of galaxies. Due to its nature, dust is very difficult to detect and quantify. This program will measure the amount of dust in the halos that surround galaxies by measuring the dimming of light sources in the background of 25 galaxies. The dimming of background sources will provide an estimate of the amount of dust surrounding these galaxies. Mapping the distribution of dust around galaxies will also help us understand the nature of dark matter. As part of this program, the PI will expand an established series of public talks given to the local community in the Tucson area. This program will also support the training of a graduate student in the field of astronomy with an emphasis on machine learning. This program aims to quantify the properties of circumgalactic dust by mapping the reddening of the many thousands of faint background sources projected near local galaxies. This work will be done with a set of 25 high-quality, extremely deep images of local galaxies to make the first measurements of halo dust in individual galaxies and demonstrate what will eventually be done with the full Rubin/LSST dataset. There is almost no work on tracing halo dust beyond the mere confirmation of its existence. Despite constituting a relatively minor component of the circumgalactic medium (CGM), this dust provides an alternative avenue for tracing chemically enriched halo material and determining the dark matter halo density profile, which in turn constrains the physical nature of the dark matter particle. 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.

Poughkeepsie

Dutchess County Bus Service Expansion

Economic Development Initiatives 17-18

Dutchess Tourism Working Capital

Market NY - RC7- DED Local Cash

Dutchess Tourism, Inc. Working Capital

Georgetown Community Council

The 'flume' is a site owned by Seattle City Light, which historically conducted water to the Georgetown Steam Plant. The site was identified by residents through the Georgetown Open Space Vision Framework plan as priority site for improvement. This project will activate the site by engaging the community in its clean up and envision how it can be improved to be safe, clean, and accessible. The community will stage an Earth Day event with the Duwamish Alive coalition, featuring a habitat restoration work party, an onsite design charrette, entertainment and children's activities.

Environmental Coalition of South Seattle

A coalition of cultural groups will produce three community-driven cultural events in August 2015 celebrating the Duwamish River traditions of First Nations, Latino, and Southeast Asian groups. The regatta will include boat tours, individual and industrial business boats, workboats, art installations and performances.

South Park Area Redevelopment Committee

The South Park Area Revitalization Committee (SPARC) proposes to hire a landscape architecture and design consultant to facilitate public input and create a schematic design, construction documents, and construction cost estimates to improve Duwamish Waterway Park. SPARC will identify features and programming that meet community members’ needs and interests.

South Park Area Redevelopment Committee

In Phase II, the South Park Area Redevelopment Committee (SPARC) will prepare construction documents and permits for Duwamish Waterway Park improvements. SPARC will continue to work with ELM Environments to facilitate a community engagement and design process.

Dwight School Foundation

Dwight School Foundation is an active grantmaking foundation based in New York, NY. Focus: general. Contact the foundation directly for current funding opportunities.

NIA - National Institute on Aging

Every year, more than 1.6 million U.S. adults experience an acute cardiovascular disease (CVD) event (i.e., acute coronary syndrome, stroke/transient ischemic attack). Over 200,000 of these adults will develop clinically significant posttraumatic stress symptoms (PTSS) that undermine health behaviors (e.g., poor sleep, physical inactivity) and increase secondary risk. Critically, acute CVD is not experienced in isolation. Partners also experience significant distress, further endangering patients’ health—and their own. Aging partners are more likely to also be patients with chronic health conditions of their own, which underscores the necessity of examining acute CVD as a dyadic experience. The proposed study will be the first to empirically evaluate the impact of couples’ distress early after evaluation for acute CVD on dyadic health and estimate dyadic influences in the progression of patient and partner distress during the first month post-event. Relationships are among the strongest predictors of mental, physical, and behavioral health. Dyadic interventions could be leveraged to improve patient outcomes. Current recommendations to bring a close other to the ED as a source of support reflect our belief in the health-promoting potential of relationships. However, our research suggests that dyadic processes differ substantially early after an acute event v. during the well- studied chronic disease phase. In this early phase, partners can increase CVD patients’ psychological distress in the ED and, subsequently, worsen their PTSS. We will leverage our ED-based research infrastructure to recruit a diverse sample of patients evaluated for acute CVD and their partners (N = 160 dyads). Data collection will include surveys at baseline enrollment and 1- and 6-months post-hospital discharge, weekly assessments of distress during the first month post-discharge, and 28 days of continuous accelerometer- derived sleep and physical activity assessment. Guided by Cornelius’ (PI) dyadic disruption theory (DDT), we hypothesize that couples’ greater distress at ED evaluation will be associated with greater PTSS, poor sleep, and physical inactivity at 1- and 6-months post- hospital discharge. We expect to reveal dyadic influences in distress progression over the first month after acute CVD and will test theory-based mechanisms of patient and partner influence. We will use qualitative inquiry to elaborate, clarify, and enhance the validity of dyadic mechanisms of health and distress progression. We will query suggestions, preferences, and barriers regarding in-hospital dyadic interventions to address key gaps limiting clinical care, including the current lack of effective interventions to prevent medically induced PTSS and the unfortunately typical neglect of partners’ needs during the sensitive window early after acute CVD. Researchers and couples facing medical stressors report high enthusiasm for dyadic interventions. If successful, results will inform the generation of implementable, mechanistic interventions that can be delivered to couples in the hospital to promote dyadic mental, physical, and behavioral health and optimal aging.