Grants

NHLBI - National Heart Lung and Blood Institute

Project Abstract Kidney Disease is prevalent in people with hypertension and is associated with adverse cardiovascular (CV) outcomes. Knowledge regarding circulating biomarkers for early detection of which patients with hypertension are at future risk for decline in glomerular filtration rate (eGFR) and adverse heart outcomes is limited. Evidence from clinical trials clearly demonstrated that effective blood pressure (BP) lowering treatment ameliorates the harmful effects of uncontrolled hypertension on adverse kidney and heart outcomes; yet, it remains unclear in which individuals intensive BP lowering will result in further GFR decline, and guidelines regarding BP target in people with hypertension, with and without baseline diabetes mellitus or chronic kidney disease, are controversial. In our previous NIH-funded research, using data from BioLINCC in people with heart failure (HF) with preserved ejection fraction, we found a subset of 6 circulating proteins (CCL16, EPHB4, IGFBP-7, LTBR, PLC, and TFF3), higher baseline levels of which were associated with adverse kidney outcomes (increase in urine albumin-to-creatinine ratio (UACR) and decline in eGFR), and also associated with a composite event of CV death, heart failure hospitalization, and aborted cardiac arrest. Our overarching hypothesis is that these proteins are also associated with decline in eGFR and increase in UACR in people with hypertension prior to the development of left ventricular hypertrophy or heart failure. We further hypothesize that intensive BP control will ameliorate the association of these biomarkers with adverse CV and kidney outcomes. We plan to obtain specimens from the Systolic Blood Pressure Intervention Trial (SPRINT), a study population with hypertension without diabetes mellitus, and the Action to Control Cardiovascular Risk in Diabetes (ACCORD), a study population with hypertension and diabetes, available in BioLINCC and use the Olink proteomics platform to measure these 6 proteins. Our other biomarkers of interest, serum creatinine and UACR, are available in the database. We will use these data to (Aim 1) determine whether higher baseline levels of a subset of prespecified blood biomarkers, CCL16, EPHB4, IGFBP-7, LTBR, PLC, and TFF3, are associated with a CV composite of non-fatal MI, stroke, CV death, congestive HF, or unstable angina in people with hypertension but without LVH or HF; and identify whether intensive BP lowering ameliorates the association; and (Aim 2) determine whether higher baseline levels of blood biomarkers, CCL16, EPHB4, IGFBP-7, LTBR, PLC, and TFF3, are associated with (a) eGFR decline and (b) increase in UACR from baseline to 3 years in people with hypertension but without LVH or HF; and identify whether intensive BP lowering ameliorates this association. We will also explore whether diabetes will modify the association of these biomarkers with the CV and kidney outcomes in people with hypertension. These biomarkers will be useful in early understanding of which people with hypertension are at increased risk of kidney function decline and adverse CV events. Moreover, identifying such biomarkers will pave the way for future studies to better understand kidney disease pathogenesis in the setting of hypertension.

NYC Department of Cultural Affairs

Association for the Development of Vocal Artistry and Neighborhood Cultural Enrichment

Regional Council Capital Fund - RC4

Association for Vision Rehabilitation and Employment Capital

Association Of Diabetes Care & Education Specialists Foundation

Association Of Diabetes Care & Education Specialists Foundation is an active grantmaking foundation based in Chicago, IL. Focus: general. Contact the foundation directly for current funding opportunities.

NYC Department of Cultural Affairs

Association of Dominican Classical Artists, Inc.

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

PROJECT SUMMARY Antiretroviral treatment (ART) is now universal. In women living with HIV (WLHIV), ART reduces perinatal HIV transmission and improves maternal health. In sub-Saharan Africa, women are surviving healthier and longer in a setting where most of the global HIV infections have occurred. However, other aspects of the lifespan for these women need monitoring and further planning. Specifically, areas related to reproductive health, fertility expectations, aging, and pre-menopause/menopause have not been adequately examined in the African setting. Although ART is effective and safe, its long-term assessment should continue to examine potential interactions with reproductive hormones (RHs) that physiologically impact reproduction and other aspects of health. These reproductive health data are scarce in Africa among aging populations. It should be realized that ART is not limited to treatment of those living with HIV; it will soon encompass wider coverage through pre-exposure prophylaxis and long-acting regimens for women living without HIV. Therefore, a longitudinal assessment of the RHs that influence conception and their potential association with infecundity, premature menopause, and menstrual irregularity is an important, unique priority to address the evolving needs of WLHIV as they age. We propose a longitudinal study of the female anti- mullerian hormone (AMH), a marker of ovarian reserve and produced by the granulosa cells of the ovary, utilizing recently collected samples from WLHIV on lifelong ART in a cohort study called “PROMOTE” (a multi-country, observational study conducted at eight African sites during 2016-2021). In the proposed study, we will use laboratory samples and data from the Blantyre site in Malawi. We have robust data already collected on sociodemographic, sexual, and reproductive health (including use of hormonal contraceptives), and clinical (including viral load and CD4 cell counts) information from baseline and at follow-up visits every six months for approximately five years. We noted an interesting observation at study completion at the Blantyre site: 112 WLHIV on lifelong ART (41% of 273 who did not have a hysterectomy or tubal ligation) never became pregnant during follow-up, and 161 (59%) became pregnant at least once. This raises a question whether HIV/ART (or other related factors) is associated with infecundability. To investigate this observation further, we will measure AMH levels at baseline and at each follow-up visit. We will compare AMH values at baseline from the PROMOTE cohort to measurements obtained from a separate control group of non-pregnant, age-matched, women without HIV recruited from the same clinics in Blantyre, Malawi. The control group will include two groups of women using/not using HCs to allow evaluation of the impact of HCs use on AMH. These data will allow us to determine the association of lifelong ART with AMH and its impact on fecundity. This exploratory study could have high reward to the scientific community involved in reproductive health management.

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

PROJECT SUMMARY Antiretroviral treatment (ART) is now universal. In women living with HIV (WLHIV), ART reduces perinatal HIV transmission and improves maternal health. In sub-Saharan Africa, women are surviving healthier and longer in a setting where most of the global HIV infections have occurred. However, other aspects of the lifespan for these women need monitoring and further planning. Specifically, areas related to reproductive health, fertility expectations, aging, and pre-menopause/menopause have not been adequately examined in the African setting. Although ART is effective and safe, its long-term assessment should continue to examine potential interactions with reproductive hormones (RHs) that physiologically impact reproduction and other aspects of health. These reproductive health data are scarce in Africa among aging populations. It should be realized that ART is not limited to treatment of those living with HIV; it will soon encompass wider coverage through pre-exposure prophylaxis and long-acting regimens for women living without HIV. Therefore, a longitudinal assessment of the RHs that influence conception and their potential association with infecundity, premature menopause, and menstrual irregularity is an important, unique priority to address the evolving needs of WLHIV as they age. We propose a longitudinal study of the female anti- mullerian hormone (AMH), a marker of ovarian reserve and produced by the granulosa cells of the ovary, utilizing recently collected samples from WLHIV on lifelong ART in a cohort study called “PROMOTE” (a multi-country, observational study conducted at eight African sites during 2016-2021). In the proposed study, we will use laboratory samples and data from the Blantyre site in Malawi. We have robust data already collected on sociodemographic, sexual, and reproductive health (including use of hormonal contraceptives), and clinical (including viral load and CD4 cell counts) information from baseline and at follow-up visits every six months for approximately five years. We noted an interesting observation at study completion at the Blantyre site: 112 WLHIV on lifelong ART (41% of 273 who did not have a hysterectomy or tubal ligation) never became pregnant during follow-up, and 161 (59%) became pregnant at least once. This raises a question whether HIV/ART (or other related factors) is associated with infecundability. To investigate this observation further, we will measure AMH levels at baseline and at each follow-up visit. We will compare AMH values at baseline from the PROMOTE cohort to measurements obtained from a separate control group of non-pregnant, age-matched, women without HIV recruited from the same clinics in Blantyre, Malawi. The control group will include two groups of women using/not using HCs to allow evaluation of the impact of HCs use on AMH. These data will allow us to determine the association of lifelong ART with AMH and its impact on fecundity. This exploratory study could have high reward to the scientific community involved in reproductive health management.

NCI - National Cancer Institute

PROJECT SUMMARY Cancer-related fatigue affects nearly all people undergoing cancer treatment and sometimes persists for months or years post-treatment. The etiology and pathophysiology of cancer-related fatigue are not well understood but may be related to disruption in circadian rhythms. Circadian rhythms describe the daily oscillations of metabolic, endocrine, and neuronal systems, all of which regulate energy levels. Behavioral interventions such as exercise and diet can regulate (or dysregulate) circadian rhythms, though circadian mechanisms are rarely leveraged in behavioral interventions. Ambulatory actigraphy data has become easy and inexpensive to collect, and there is a plethora of methods to analyze rest-activity rhythms from actigraphy data. However, timing is rarely incorporated into behavioral programs to address fatigue because the field has not yet defined unequivocal rest- activity rhythm parameters from actigraphy datasets that are associated with fatigue. Thus, the objective of this project is to quantify the associations between rest-activity rhythm parameters and persistent cancer-related fatigue using a battery of analysis methods. This study leverages the Harvest for Health study, which was a randomized controlled trial among older cancer survivors testing the effects of a 1-year gardening intervention vs. waitlist control. The dataset has actigraphy and fatigue data for 279 participants over two years. Participants wore an actigraph for 7 days and reported fatigue at baseline, 1 year, and 2 years. We will use traditional methods to quantify rest-activity rhythms (i.e., cosinar analysis, non-parametric measures) as well as novel hidden Markov modelling, based on a probabilistic framework. The hidden Markov models go beyond traditional methods in that they provide visual Day Profiles of activity and can quantify where in the day circadian disruptions are occurring. Aim 1 will assess the association between the rest-activity rhythm index parameters and fatigue from baseline to 1 and 2 years. We predict that higher hidden Markov-derived rhythm indices and other parameters that reflect stronger rest-activity rhythms will be associated with less fatigue. Aim 2 will assess the changes in rest-activity rhythm parameters over time. We predict that rest-activity rhythms will get stronger over time, as people get further from cancer treatment. Aim 3 will test the effects of the gardening intervention vs. control on Hidden Markov model-derived rhythm indices. We hypothesize that the gardening intervention will result in higher average rhythm index (stronger rest-activity rhythm) than the control at year 1. These findings will immediately be useful to researchers in the optimization of behavioral interventions (e.g., exercise, nutrition, sleep hygiene) to strengthen biological rhythms, address fatigue, and improve quality of life in cancer survivorship. The results and the resultant code to easily run hidden Markov models will inform future research and clinical applications. For example, these models will inform personalized recommendations for people struggling with fatigue based on a person’s rest-activity rhythm—should we focus efforts to improve sleep, encourage morning activity, minimize nutrient intake in the evening, or something else?—thereby accelerating people’s recovery from cancer.

NIAAA - National Institute on Alcohol Abuse and Alcoholism

Women are more likely to experience health impacts from risky drinking behaviors than men. One cause of this disparity is stigma, which refers to conditions, norms, and policies, including attitudes about women' s alcohol use, treatment seeking, and prenatal alcohol exposure. Stigma also has intergenerational impacts, evidenced by its adverse effects among children and infants across exposed groups. However, little is known about when stigma is most harmful across the lifecourse for women and the extent to which intergenerational effects impact offspring health behaviors. Further, the mechanisms of these intergenerational effects are underexplored, as are the moderating risk and preventive factors. These knowledge gaps contribute to perpetuating alcohol-related health consequences and limit our understanding of what factors may reduce risk among women and their children. It has not been previously possible to examine these associations because doing so requires a unique data structure with: 1) a large number of women living in different places and measured over their lifecourse; 2) longitudinal stigma measures, which are very limited; and 3) alcohol measures among both parents and offspring. This mentored research proposal will provide the first opportunity to address these questions by pairing training in stigma measurement over time using natural language processing (NLP) with data from two unique, intergenerational cohort studies: the Nurses' Health Study 2 (N=116,429), and their offspring in the linked Growing Up Today Study (N=27,704). By leveraging NLP on a corpus of >9,000 unique, digitized newspapers from all 50 US states during the lifecourse of respondents in the Nurses' Health Study 2 (75 years), I will develop and extensively validate a time-varying measure of stigma related to women' s alcohol use (Aim 1). I will then elucidate the association between stigma and alcohol use across the lifecourse among women (Aim 2) and their offspring (Aim 3) and examine which intervenable, modifiable characteristics moderate the effects of stigma. Advanced training in NLP and lifecourse epidemiology will provide the necessary tools to develop a novel stigma measure and test its relationship with alcohol consumption among women and their offspring across the lifecourse, representing a critical next step for understanding and decreasing alcohol-related health outcomes. This award is highly consistent with NIAAA' s strategic plan for reducing stigma and identifying causes of alcohol and prenatal alcohol related stigma. The proposed studies are the essential next step towards

NIEHS - National Institute of Environmental Health Sciences

ABSTRACT Per- and polyfluoroalkyl substances (PFAS) are toxic chemicals of significant public health concern due to their nearly indefinite persistence in the environment and widespread human exposures from contaminated drinking water, food, and consumer products. There is mounting evidence that PFAS exposures during gestation are associated with adverse health effects in childhood, including worse metabolic, vascular, and bone health. However, it is currently unknown whether these effects persist into adulthood. Further, as more communities discover historical PFAS exposures, there is an urgent need to identify interventions to mitigate adverse effects of PFAS exposures after they have already occurred. To address these critical knowledge gaps, the goals of this proposal are to estimate the impact of the effects of prenatal PFAS mixture burden on mid-adulthood health and to evaluate factors that may mitigate these effects. We will accomplish our aims using the New England Family Study (NEFS), a unique prospective cohort study of pregnancies in the 1960s with data collected from children annually from birth through age 7 years, and again in mid-adulthood (mean age=47 years, n=400). NEFS is an ideal cohort to address our aims, as it has amassed rich data from pregnancy through mid-adulthood including detailed adult health phenotyping. We will additionally measure concentrations of 44 PFAS in stored serum samples collected during pregnancy and adulthood. Using state-of- the-art analytical approaches to quantify PFAS mixture burden, we will determine whether prenatal PFAS burden is associated with worse metabolic function, vascular health, and bone mineral density in mid- adulthood, independent of concurrent PFAS burden (Aim 1) and assess whether adverse impacts are stronger among those with suboptimal diet quality and physical activity (Exploratory Aim). Our team of experts in exposure assessment, analytic chemistry, biostatistics, environmental epidemiology, and clinical medicine will be the first to examine long-term effects of PFAS mixture burden on multiple prevalent adult health outcomes, and to inform potential interventions to reduce the impact of prior exposures. Our findings will serve as the basis for a future follow-up of NEFS participants to elucidate the adult health impacts of early life PFAS exposures on metabolic, vascular, and bone health outcomes. Ultimately, this research will provide critical evidence on the long-term impacts of PFAS exposures to inform health screening guidance in PFAS-exposed communities, refine proposed PFAS drinking water regulations, and identify potential interventions to reduce the health impacts of historical PFAS exposures.

NHLBI - National Heart Lung and Blood Institute

Abstract Every year in the United States, tens of thousands of children are placed on mechanical ventilation, of which an estimated 1 in 5 are at risk of serious complications. Complications in these environments commonly arise from airway trauma, inadequate oxygenation, and aspiration leading to infection. At the root of many of these complication risks come from the device that connects the patient to the ventilator – an endotracheal tube (ETT). For decades, ETTs have used an inflatable balloon to create a seal in the airway to seal the airway and prevent aspiration and enable ventilation. The problem is that these balloons are failure points for patients and providers. The balloons often crease leading to increased aspiration risk, or can be easily overinflated, leading to increased risk of trauma and collapse. Additionally, most ETTs in pediatrics were not originally designed with balloons in mind, as they were historically uncuffed. In this transition, there remains a high uncertainty that today’s tools adequately help tomorrow’s children. To solve this problem, Respair developed AssuranceET, a pediatric first ETT that replaces the error-prone balloon with ultra-soft micro-baffles (thin, flexible discs) and has a smaller outer diameter. The micro-baffles gently fold along the trachea wall to comprehensively seal the airway while exerting less force than a balloon. In preliminary testing, RelianceET was 98% more effective than current ETTs in preventing leaks. Respair conducted over 300 interviews with clinicians and purchasers to map the needs of key stakeholders. What remains unknown is if the baffle sealing mechanism is safe and effective for pediatric airway sizes. This SBIR has two specific aims to achieve critical milestones that assess the feasibility of AssuranceET in pediatric airways. Aim 1: Develop high-fidelity pediatric airway models using CT scan reconstructions and 3D printing. Respair will develop high-fidelity pediatric airways using published data from CT scans to create clinically relevant test models for comparative testing of AssuranceET and competitor tubes. Aim 2: Complete comparative leak, tracheal pressure, and ventilatory pressure tests on AssuranceET prototypes and standard ETTs. Respair will test AssuranceET prototypes and competitors using enhanced test protocols to quantify critical safety metrics that validate the baffle sealing mechanism across pediatric airway sizes Completing these objectives will validate AssuranceET’s technical feasibility and safety, enabling Respair to reach a final design freeze. Respair aims to create a new standard for critical care by commercializing a safer and more effective endotracheal tube to improve outcomes for vulnerable patients on ventilators.

Café Chingon LLC

Astoria Coffee Company Expansion

Reach Break, LLC

Astoria Expansion

NYC Department of Cultural Affairs

Astoria Film Festival Inc

Innovative Housing Inc.

Astoria Merwyn Assessment Cleanup Project

Blue Jumpsuit, LLC

Astoria Warehouse Property Cleanup Project

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY/ABSTRACT Idiopathic subglottic stenosis (iSGS) is a debilitating and life-threatening disease where scar tissue narrows the airway, severely limiting an individual’s ability to breathe and communicate. The cause is not completely delineated but appears related to the activation of a pro-inflammatory cascade. Treatment is procedural with the goal of increasing airway diameter to improve breathing. The most commonly employed treatment approach is intermittent endoscopic dilation, typically performed every 12-18 months. Adjunctive methods to prolong the period between operations are highly desirable to the iSGS patient community. One promising potential adjunctive method is serial intralesional steroid injections (SILSI), or serial injection of steroids into the affected airway in the clinic setting. While initial single-institution retrospective series showed potential for prolongation of the inter-operative interval, secondary analysis of a multi-institutional prospective cohort study did not show a clear benefit. Given disparate results and the importance of developing effective adjunctive methods, a prospective randomized trial is critical to evaluate the effectiveness and determine which iSGS patients may benefit most from this adjunctive treatment. CCC MPIs, Drs. Alexander Hillel and Alexander Gelbard, along with DCC MPIs, Drs. Dan Hanley and Gayane Yenokyan, will lead a multicenter, prospective, randomized, double- blinded, placebo-controlled trial titled, ASTRO: Adjuvant STeRoid injection Outcomes in idiopathic subglottic stenosis. This trial was developed in partnership with both patient and clinician stakeholders and is designed to evaluate the safety and efficacy of SILSI in iSGS patients. 226 iSGS participants will be recruited across 10 high- volume academic sites and randomized to SILSI or placebo (intralipid preparation simulating appearance of triamcinolone) in a 1:1 ratio following a standardized endoscopic dilation. Participants will undergo a series of three injections, spaced one month apart and beginning one month after endoscopic dilation. Our primary outcome measure is percent peak expiratory flow, which is a biomarker of disease recurrence in iSGS. The study aims are to: (1) Compare change in peak expiratory flow in iSGS patients with and without adjuvant SILSI from 1 month to 6 months after endoscopic dilation (primary endpoint) and 1 month to 12 months after dilation (secondary endpoint); (2) Compare secondary outcomes in iSGS patients with and without adjuvant SILSI including patient-reported outcome measures of breathing, QoL, voice, and swallow function as well as toxicity profile and safety events, including return to the operating room for a recurrent procedure and death; and (3) Characterize heterogeneity in SILSI treatment response based on demographic, clinical, surgeon, and genomic characteristics as assessed using established single nucleotide polymorphisms (SNPs) proven to dictate steroid responsiveness in patients with asthma. This represents the first interventional trial in iSGS and fills a critical knowledge gap by assessing the efficacy and safety of SILSI for iSGS, providing an evidence-based foundation to change clinical practice.

NIA - National Institute on Aging

Abstract Lewy body dementia (LBD) is the second most common form of dementia after Alzheimer’s disease (AD), affecting over 1.4 million Americans. The causes of LBD remain largely unknown, and there is currently no cure. This application aims to explore the mechanisms that underlie the genetic link between LBD and mutations in GBA1, the gene that encodes the lysosomal enzyme glucocerebrosidase (GCase). Homozygous recessive mutations in GBA1 cause Gaucher disease, the most common lysosomal storage disorder, which is often associated with parkinsonism and cognitive impairment. Heterozygous GBA1 mutations, however, represent the strongest genetic risk factor for both LBD and Parkinson’s disease (PD), and are linked to more severe cognitive impairment and more rapid cognitive decline. Despite the role of GBA1 mutations in promoting α-synuclein (αSyn) pathology, little is known about how these mutations contribute to the pathophysiology of LBD. Using an astrocyte specific Gba1 conditional knockout (Gba1CKO) mouse model, we have found that astrocyte Gba1 deficiency induces hippocampus dependent mild cognitive impairment. By crossing Gba1CKO mice with the well- characterized Thy1-αSyn (Line 61) mouse model of LBD, which overexpresses human wild-type αSyn, we provide evidence that astrocyte Gba1 deficiency exacerbates LBD-related αSyn accumulation, cognitive impairment and motor symptoms. Gba1CKO mice further demonstrate an increase in levels of hippocampal astrocyte GABA transporter GAT-3, a reduction in extrasynaptic GABAAR-mediated tonic inhibition in CA1 pyramidal neurons, and a defect in autophagy-lysosome degradation. Based on these preliminary findings, we hypothesize that GBA1 deficiency disrupts astrocyte GAT-3-mediated GABA uptake and tonic inhibition, leading to increased neuronal excitability and more severe αSyn accumulation during the prodromal phase of LBD. Three specific aims are proposed: Aim 1 will determine whether GAT-3 upregulation contributes to impaired tonic inhibition and neuronal hyperexcitability in Gba1CKO mice; Aim 2 will assess whether GAT-3 upregulation is caused by autophagy-lysosome dysfunction in Gba1CKO mice; Aim 3 will examine whether impaired tonic inhibition exacerbates neuronal hyperexcitability and αSyn pathology in the Gba1CKO:Thy1-αSyn LBD model mice. The successful completion of this project will reveal a novel astrocyte-mediated mechanism for LBD pathogenesis and inform the development of more effective therapies.

U.S. National Science Foundation

Astronomy and Astrophysics Research Grants

NIBIB - National Institute of Biomedical Imaging and Bioengineering

Abstract The quantitative detection of nucleic acids plays an increasingly important role in the early detection and screening of cancers. Although the real-time quantitative PCR method has become the gold standard for nucleic acid quantification, its reliance on expensive equipment and trained personnel limits its use in resource-limited settings. Recently, CRISPR technology has emerged as a simple and powerful tool for highly sensitive and specific nucleic acid detection when combined with nucleic acid pre-amplification. However, due to the incorporation of the pre-amplification step, CRISPR-based detection methods require multiple operations and lack the quantitative detection capabilities needed for nucleic acid targets. Therefore, developing a simple and sensitive CRISPR approach for the quantitative detection of nucleic acid biomarkers (e.g., microRNAs) remains a challenge. Recent studies have demonstrated that exosomal microRNAs (exo-miRNAs) are promising liquid biopsy biomarkers for detecting cancer progression and assessing therapy efficacy with high sensitivity and specificity. However, current methods for exo-miRNA detection often require expensive equipment and specialized expertise, hindering their widespread clinical application. Here, we propose to study an asymmetric CRISPR approach for the quantitative detection of nucleic acids (e.g., exo-miRNAs). Furthermore, we will integrate the asymmetric CRISPR assay into a microfluidic chip to develop an asymmetric CRISPR diagnostic platform for exo-miRNA profiling in clinical blood samples. As an example application, we will adapt our asymmetric CRISPR diagnostic platform for the non-invasive early detection of breast cancer—the most commonly diagnosed cancer in the world—and rigorously validate its clinical application. Ultimately, the success of our proposed project will enable clinical translation, facilitating the development of a simple, sensitive, nucleic acid-based molecular detection method for early cancer detection and personalized medicine.

NIGMS - National Institute of General Medical Sciences

Project Summary This proposal centers on developing new deoxygenative functionalization of alcohols and carboxylic acids for accessing medicinally valuable chiral amines and fluorinated compounds through new sequential, stereo- controlled reactions. Alcohols and carboxylic acids are ubiquitous, structurally diverse, and stable feedstock chemicals, making the asymmetric deoxygenative diversification of their C–O bonds a highly attractive strategy for exploring new chemical space and discovering new therapeutics. While seminal approaches have demonstrated converting alcohols and carboxylic acids to pharmaceutically relevant chiral products, these methods often require multiple steps, undergo slow C–O bond activation, are limited in nucleophile scope, and lack stereo-control. To overcome these challenges, the Kim Group will employ a sulfonyl fluoride as a SuFEx (Sulfur Fluoride Exchange) clickable reagent for alcoholic C–O bond activation and a catalytically versatile base metal that will facilitate multiple C–O bond functionalizations of carboxylic acids. Our methods will allow one- step, rapid asymmetric C–O bond derivatization to construct C(sp3)–N/C bond formations between unfunctionalized starting materials and diverse nucleophiles with predictable stereochemical outcomes. Herein, we will develop the following Research Programs: (1) One-step, stereospecific and site-selective deoxygenative amination and perfluoroalkylation of alcohols via SuFEx, allowing direct installations of pharmaceutically relevant free amines, N-heterocycles, and perfluoroalkyl groups into alcohols, and (2) enantioselective deoxygenative diversification of carboxylic acids, providing a new platform for chiral amine synthesis via sequential geminal C– O bond functionalizations of a carboxyl group. Together, the successful realization of the goals described in these research programs will provide a new set of robust tools for rapid asymmetric derivatization of C–O bonds within widely available feedstock chemicals and complex molecules, which will expedite synthetic access to medicinally valuable products.

NSF

Many biological and physical systems exhibit high degrees of internal complexity that resist direct mathematical description. Examples include ecological dynamics in a varied environment and fluctuating flame fronts in combustion. Nonetheless, such systems often exhibit tractable behavior when viewed at large or fine scales. This "asymptotic" behavior plays a major role in applications, and often has a universal character that unites the study of disparate systems. In this project, the principal investigator (PI) will combine several mathematical methods to identify and justify asymptotic phenomena in partial differential equations (PDEs) originating in the sciences. This work has the potential to shed light on a variety of systems including ecological invasion, atomic deposition, and fluid shock formation. The PI is committed to undergraduate and graduate mentorship, with the particular aim of supporting students from underrepresented backgrounds. This project will explore the asymptotic behavior of various deterministic and stochastic PDEs in significant limiting regimes. The project comprises three interconnected lines of work. (1) The PI will study the long-time propagation speed and front structure of solutions to reaction-diffusion equations in heterogeneous and random environments. This investigation encompasses a dual analysis of associated branching particle systems. (2) The PI will combine analytic and probabilistic methods to study long-time and white-noise limits of several physically motivated stochastic PDEs, including stochastic conservation laws and stochastic heat equations near criticality. (3) The PI will investigate the action of weak viscosity on internal shock formation in the compressible Navier--Stokes equations. This involves a delicate coupling between hyperbolic and parabolic approximations. 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

This project seeks to advance the mathematical analysis of plasma physics and rotating fluids. Plasmas are ubiquitous in astronomy and in geophysical fluids. They are also central to many challenges and opportunities facing the modern world, from neon lamps to fusion reactors. The many scales involved, and the very unstable nature of plasmas represent formidable challenges and require many different levels of description whose precise relationship (when to use one instead of the other, and which to believe if the results disagree) is still poorly understood. Since the Earth spins, all questions involving geofluids, such as weather predictions, necessitate delicate analysis of rotating fluids. One of the throughlines of this project is that, in some special cases, the more complicated settings may actually be better behaved or more stable than one would a priori expect; for example, a fluid in rotation may be more predictable than a fluid (almost) quiescent. Isolating such favorable situations in rotating fluids and plasma physics, and understanding how and why predictions are easier then, is one of the main goals of the project. Some of the problems addressed relate to the interaction between a charged, hot gas and a solid wall bounding it; how, in the absence of boundary, a hot plasma may be stabilized under a reversible phenomenon called ``Landau damping'' or whether a faster spinning Earth would have a simpler weather system. The project provides research training opportunities for graduate students and postdoctoral scholars. This project studies partial differential equations inspired by physics. The first part of the project concerns the description of the asymptotic behavior of solutions to non-collisional kinetic equations. The Principal Investigator (PI) studies the stability of homogeneous equilibria for the Vlasov-Poisson system, starting with the case of fat-tail equilibria, as well as the stability of vacuum for the same system in the presence of boundaries. Extensions to more involved models (e.g. Vlasov-Maxwell), will also be considered. The second part of the project addresses problems related to quasilinear dispersive equations. The PI studies the derivation of the Euler-Poisson system for ions from the two-fluid model in the case of confined domain and also investigates the stability of a constant background at rest for the compressible Euler equations in a rotating environment. These problems are addressed using tools from finite dimensional Hamiltonian dynamical systems, harmonic analysis, atomic spaces, functional analysis and more standard partial differential equations tools like the maximum principle, energy estimates, bilinear estimates and precise dispersion analysis. 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.

Public Health Agency of Canada | Agence de la santé publique du Canada

The Office of Audit and Evaluation (OAE) Departmental Evaluation Plan for PHAC describes the Program Evaluation Division's scheduled work for the five-year period from 2021-22 to 2025-26. The Plan was developed to meet PHAC's commitments under the Policy on Results (2016), which requires that each department prepare a five-year plan, annually updated. The projects included in this Evaluation Plan were selected to ensure full coverage of all Grant and Contribution spending over $5 million annually over a five-year period, prior commitments in Treasury Board Submissions, the information needs of program management, and program risks, and optimal use of resources. The Departmental Results Framework (DRF), program inventory, and performance information profiles developed by PHAC have formed the basis for this plan.