Grants

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary/Abstract Significance: Access to insulin, a biologic drug, has become a burden for many patients due to high prices. Biosimilars offer a solution to overcome this burden. They are biologics that are highly similar to the originator- biologic but not an exact copy. They are designed to match the structure and clinical effects of the originator- biologic. In July 2021, insulin glargine-yfgn (Semglee) became the first interchangeable biosimilar insulin approved. However, the randomized trials used to support the approval of Semglee were small in sample size, short in duration, and lacked diversity. Thus, there is an urgent need for real-world evidence on the use and safety of Semglee compare the originator-biologic insulin glargine (Lantus). Specific Aims: The proposed project will provide valuable information to patients and stakeholders on the use and safety of Semglee in a real-world population and demonstrate novel pharmacoepidemiology methods to evaluate the safety and interchangeability of biosimilar insulins post-market approval. In Aim 1, we will quantify and characterize the switching patterns (e.g., Lantus-Semglee-Lantus) of patients who received a prescription for Semglee or Lantus and assess their characteristics to understand how patient characteristics influence biologic and biosimilar insulin use. In Aims 2 and 3, we will use novel pharmacoepidemiology methods to replicate and emulate the randomized trials used to support the approval of Semglee with real-world data and compare the rate of serious hypoglycemia between Semglee and Lantus. Approach: This study will compare the use and safety of Semglee to Lantus with real-world data from the Merative MarketScan database, a longitudinal administrative claims database of more than 250 million private insurance beneficiaries. In Aim 1, we will identify switching patterns (e.g., Lantus-Semglee-Lantus) among patients who received a prescription for Semglee or Lantus and assess their demographics and clinical characteristics at baseline, `time of first switch', and `time of first switchback'. In Aim 2, we will compare the rate of serious hypoglycemia between Semglee and Lantus over a 1-year follow-up period with the prevalent new- user study design. In Aim 3, we will emulate a randomized switching trial to compare the interchangeability (effect of switching) between Semglee and Lantus to continuous (non-switching) Lantus on the rate of serious hypoglycemia over a 9-month follow-up period with the clone-censor-weight approach. Fellowship Information: The principal investigator is a PhD student in Epidemiology at UNC. Dr. Her proposes a training plan that will equip him with the knowledge and skills to launch a career as an independently funded principal investigator in diabetes. His training plan consists of mentor research, coursework and seminar, and professional development that will take place in a thriving collaborative research environment, guided by an internationally recognized team of mentors.

NHLBI - National Heart Lung and Blood Institute

Project Summary Hematopoietic stem cells (HSCs) sustain blood production throughout an organism’s lifetime. They are clinically significant as the key therapeutic component of bone marrow transplants for treating a multitude of hematological and non-hematological disorders. However, HSC transplantation is limited by scarcity of compatible donors. Despite significant efforts, generating large numbers of bona fide HSCs in vitro from induced pluripotent stem cells (iPSCs) remains a major challenge. This inability likely stems from an incomplete understanding of the developmental cues necessary for HSC specification. In vertebrate embryos, HSCs are specified from hemogenic endothelium lining the ventral wall of the dorsal aorta (DA) and require signals from the surrounding microenvironment. Previous work in our laboratory demonstrated that neural crest cells (NCC) migrate to the DA and direct HSCs specification in zebrafish via locally secreted or displayed signals. NCCs of the trunk differentiate into sympathetic neurons, which secrete catecholamines. In mice, catecholamines are required for HSC maturation. However, inhibition of catecholamine production in zebrafish did not affect HSC specification, pointing to the idea that an earlier phase of HSC specification directed by NCCs is independent of catecholamines. Although HSC programming is highly conserved across vertebrates, the requirement for NCCs in specifying HSCs has not yet been examined in mouse, and the cues provided by NCCs for HSC specification remain elusive. My preliminary data in mouse reveal that NCCs migrate into proximity of the DA during the HSC specification window and are found closely associated with nascent HSCs locating them at the right time and place to provide inductive signals for HSC specification. Interestingly, preliminary data in mouse and zebrafish show that NCCs do not contact the DA directly, except via filopodial extensions. To determine whether NCCs mediate HSC specification in mouse, I will map the association of migrating NCCs to the DA and emerging NCCs by lineage tracing and specifically ablate NCCs before they reach the DA with an inducible diphtheria toxin receptor mouse model. Finally, I will determine if NCCs mediate HSC specification through filopodial communication with the DA by generating a novel optogenetic zebrafish line permitting tissue specific knock out of Myosin X, required for filopodia formation and maintenance, in living animals and visualize any loss of HSCs using advanced live imaging technology.

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

Abstract Neonatal jaundice remains a challenge globally, contributing to significant newborn morbidity and mortality in low- and middle-income countries. This proposal, “Comparing a low-cost, hand-held icterometer to transcutaneous and serum measurement of neonatal bilirubin among dark-skinned infants: Can jaundice screening be improved in low-resource settings?” builds on previous validation research of the Bili-RulerTM, a hand-held icterometer developed at Harvard University. The Bili-Ruler has 6 digitally standardized strips of increasingly yellow hue that allow for comparison against blanched newborn skin. Previous research demonstrated acceptable diagnostic testing metrics in measuring elevated bilirubin, yet data are limited by a small sample size in patients of African descent, raising questions as to how effective the Bili-Ruler is among dark-skinned infants. We propose to conduct a robust validation study among newborns in Kumasi, Ghana, in West Africa (where 99% of the population is from one of 10 African ethnic groups) to address this gap in understanding. We aim to test the Bili-Ruler against both transcutaneous (TCB) and serum (TSB) bilirubin measurements among Ghanaian newborns to determine if this low-cost, hand-held device is a viable option to improve jaundice screening and monitoring in sub-Saharan Africa. Our study includes the following aims: Aim 1: To determine screening accuracy of the Bili-Ruler, we will compare healthcare providers’ Bili- Ruler assessments with measures of TCB on 2000 newborns and TSB on 400 newborns. We will use gestational age at birth, hours since birth, and risk factors for jaundice to determine if TCB and TSB levels are above the recommended threshold for treatment, and we will compare findings against newborns judged to have Bili-Ruler scores of 3 or higher. We will calculate sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) for the Bili-Ruler against TCB and TSB. Aim 2: To determine differences in the Bili-Ruler’s accuracy based on both underlying skin tone and severity of jaundice, we will use scores on the Monk Skin Tone Scale (range: 1-10) and increasing thresholds on the Bili-Ruler (e.g. 3+, 4+, 5+) to explore differences in sensitivity, specificity, PPV, NPV and AUC for the Bili-Ruler against TCB and TSB, using healthcare providers’ assessments. Aim 3: To determine inter-rater reliability, we will compare healthcare providers’, researchers’ and mothers’ scores on the Bili-Ruler using correlation, Kappa, and McNemar’s statistical tests. This research is innovative in that it seeks to determine whether a simple, low-tech, hand-held “ruler” could be used as a valid screening tool for neonatal jaundice. If so, the implications for jaundice screening in low- resource settings is significant, given that screening could then be conducted at lower-level facilities or in remote communities without access to TCB and TSB assessments.

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

Project Summary Increased availability of high-energy dense foods has contributed to a pediatric obesity epidemic, with 23% of United States children currently presenting with the disease.11 Recently, laboratory studies identified an ‘obesogenic’ style of eating marked by larger bites, and faster eating and bite rates.12,13 This highlights that how children eat contributes to both overconsumption12,14 and greater adiposity.13,14 These components of ‘eating microstructure’ have been proposed as modifiable behavioral targets for obesity prevention.15,16 However, it is unclear if laboratory measures of children’s eating style generalize to the home environment, where children consume two thirds of their total energy.17–19 NICHD’s Pediatric Growth and Nutrition Branch emphasizes the importance of identifying early risk factors for childhood obesity, therefore, the proposed study will use a smart-phone based research platform to 1) test if child eating styles observed in the lab generalize to more ecologically valid home environments and 2) identify aspects of home food environment that amplify obesogenic eating behaviors. We will assess laboratory and home eating styles (e.g., bite rate) in 100 prepubertal 6-9-year-old children to constrain variability in energy requirements.20 Children will be video-recorded while consuming identical study-provided meals at home and in the laboratory (counter-balanced order) in addition to a ‘typical’ meal at home. Parents will use smart-phone devices and the Wear-IT app10 to video-record children at home. To study how adiposity relates to “obesogenic” styles of eating, gold standard dual x-ray absorptiometry49 will be used. We hypothesize children will have a consistent eating style in the laboratory and at home and that regardless of meal environment or composition, children with higher adiposity will have more obesogenic styles of eating (e.g., faster bite rate, larger bites) compared to children with lower adiposity. Parents will also report social (e.g., feeding practices21) and physical (e.g., foods available22) characteristics of the home food environment, as these can influence child eating behaviors. We hypothesize that home food environments characterized by greater availability of energy dense foods, greater access to technology during meals, and less frequent family meals will be associated with a more obesogenic eating style in the home than the laboratory. The ability to target eating behaviors that drive overconsumption is critical for the prevention of pediatric obesity, a primary goal of NICHD’s Pediatric Growth and Nutrition Branch. Assessing eating behaviors in ecologically valid home settings is a critical step in the prevention overconsumption and obesity. The proposed virtual platform will also lay the foundation for other areas of child health that rely on manual coding of behaviors (e.g., communication, human development, and clinical psychology), setting the stage for longer-term impacts. The use of smart-phone devices also reduces barriers to research and clinical participation for rural and underserved populations (e.g., proximity to research/care centers, transportation) by providing a virtual platform to engage families in their home.

NSF

This project develops a new method for comparing human and artificial intelligence (AI) decision-making, generating insight on how to combine human and AI input in high-stakes decisions like medical diagnoses. While researchers can easily observe an AI tool’s prediction process, human decision-making is more complicated. For example, a radiologist’s diagnostic decisions may reflect both their judgments about the presence of cancer and their assessments of the cost of an incorrect diagnosis, but researchers often only observe their final decision. This project develops a method for comparing human and AI decision-making that accounts for complex human preferences and judgements caused by factors that the researcher cannot directly observe. The researchers apply these methods to a radiology setting, using data from a large clinical trial to compare an AI tool’s predictions of lung cancer to radiologists’ diagnoses. This research helps determine the optimal use of AI in high-stakes decisions by answering questions like the following: What valuable information do humans infer that AI assessments miss? What are the intricacies of human preferences during decision-making, and how do these intricacies affect the quality of human decisions compared to AI decisions? This research generates insights that can be used to design better AI-supported decision systems in radiology and other high-stakes settings, leading to public health benefits, a deeper understanding of human and AI decisions, and more responsible use of AI. The project makes three methodological and empirical contributions. First, the researchers show that commonly used approaches for comparing human experts against predictive algorithms are biased in favor of algorithms if the preferences of human experts vary due to factors not observed in the data. Second, the researchers construct bounds on the quality of human expert predictions in the presence of unobserved preference heterogeneity and identify in which specific cases the human expert observes useful private information. Third, the researchers characterize the distribution of preferences across human decision-makers and cases. In an application, the project uses data from the National Lung Screening Trial to compare an AI tool for lung cancer detection against radiologists, empirically quantifying the importance of private information observed by humans that is missed by the AI tool and the extent of preference heterogeneity across cases and radiologists. Using these results, the researchers consider two practical problems: the delegation of cases to humans or AI based on case characteristics, and the design of an automated decision-making tool that aligns AI predictions with the newly determined bounds on human decision-maker preferences. 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.

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

PROJECT SUMMARY/ABSTRACT Infants born preterm do not grow as well as their term counterparts. Poor growth during the neonatal intensive care unit admission is associated with worse neurobehavioral outcomes. Furthermore, poor infant growth and neurodevelopment have been linked with gut microbial changes. One protective driver of the infant gut microbiome is the consumption of parent’s own milk (POM). POM contains its own microbiome and human milk oligosaccharides (HMOs) unique to each parent-infant dyad. HMOs and the milk microbiome contribute to the infant gut microbiome. However, many preterm-delivering lactating parents do not have sufficient POM, requiring supplementation with donor human milk (DHM). DHM is pasteurized and pooled from multiple, mostly term donors, which likely alters HMO composition and decreases live bacteria. We hypothesize that these differences between POM and DHM likely alter the preterm infant gut microbiome and reduce the infant’s growth from birth to 36 weeks corrected gestational age. To test this hypothesis, we will leverage ongoing sampling from a funded cohort of parent-infant dyads born between 24 to 32 weeks gestation of age to examine milk microbiome (live and nonviable), HMO composition, and how these relate to infant gut microbiome and infant growth. The Specific Aims are to: 1) determine the milk microbial and HMO composition of preterm POM collected at weeks 1, 4, and 8 postpartum compared to DHM; 2) evaluate which HMO and milk microbiota (live and nonviable) are associated with infant gut microbial diversity and composition at weeks 1, 4, and 8 of age; and 3) evaluate which HMO, milk microbiota, and stool microbiota are associated with anthropometric z-score changes from birth to 36 weeks corrected gestational age. We will utilize high performance liquid chromatography for HMO analysis, metagenomic sequencing to characterize milk and stool microbiome, and propidium monoazide to distinguish live versus nonviable bacteria in milk. Growth will be measured by changes in weight, length, and head circumference z-scores from birth to 36 weeks corrected gestational age. Career Development Objectives are to 1) acquire essential knowledge in milk as a bioactive system by gaining advanced skills in systems biology and experimental design, 2) develop core competencies in multi-omic clinical- translational trial design and bioinformatic analysis, and 3) attain sophisticated skills in ethical and equitable study management, scientific writing, presentation, and grant preparation. After completion of the career development objectives and the research specific aims, the applicant will be well-positioned to obtain external funding and conduct clinical-translational studies on nutrition and growth in vulnerable parent-infant dyads. Study Impact: This study will identify critical differences between POM and DHM and their impact on the preterm infant gut microbiome and growth. The data will inform potential pre-biotic and pro-biotic supplementation for DHM in future randomized, placebo-controlled trials.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT Diverticulitis is a disease marked by inflammation of diverticula in the colon. In the US, it is highly prevalent and costly, accounting for more than 2.6 million outpatient visits (combined emergency department and ambulatory clinic) and 200,000 inpatient admissions for diverticulitis at a cost of more than $2 billion. Patients can present with a wide spectrum of disease severity, from localized inflammation (uncomplicated) to frank perforation (complicated). Traditionally in the US, treatment for acute uncomplicated diverticulitis (AUD) has been antibiotic therapy. However, antibiotics can have significant side effects, both on the patient and population level. Patients can experience side effects as well as life-threatening superinfections. At the population level, inappropriate antibiotic use is the primary driver of antimicrobial resistance (AMR), a critical national and global threat. Results from recent studies conducted in Europe suggest that antibiotics may be unnecessary to treat mild acute diverticulitis. However, these trials have significant flaws and concerning trends in secondary outcomes which have limited implementation in a US population. Additionally, the US population differs fundamentally from the European population in race and ethnicity as well as the effect of socioeconomic drivers of health. A recent study cites the lack of US data as the strongest barrier to implementation. This knowledge gap – whether antibiotics improve recovery from AUD in current US clinical practice – leads to the proposal of a pilot, randomized trial of placebo versus antibiotic treatment of AUD in 100 patients with oversampling based on race and ethnicity. We aim to 1) determine differential rates of recruitment, treatment acceptance/adherence, cross-over, clinical endpoint assessment compliance and loss to follow-up at 30 days and 6 months by race and ethnicity to assess feasibility of a large scale, multicenter trial. 2) acquire preliminary data regarding the effects of a placebo compared to antibiotics for AUD on a range of key patient-centric efficacy and safety endpoints These results will inform the design, sample size, and endpoint selection for the subsequent efficacy trial that will generate critical evidence to assess the role of antibiotics in the treatment of AUD. This proposal is an outstanding fit for PAS-23-086 (Small R01s for Clinical Trials Targeting Diseases within the Mission of NIDDK). This small, short-term clinical trial in humans will acquire preliminary data regarding the effects of non-antibiotic management of acute, uncomplicated diverticulitis, as well as feasibility data related to recruitment and retention, and study conduct. Completion of this award will lay the foundation for larger, multicenter clinical trials to further our understanding of the optimal role of antibiotics in the management of acute uncomplicated diverticulitis.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract Systemic Salmonella infections have three main infectious causes (Typhi, Paratyphi, and a group of non- typhoidal serovars). Although new conjugate vaccines exist for Typhi, there are still no licensed vaccines for Paratyphi or non-typhoidal disease, despite the fact that they account for more than 50% of deaths due to systemic Salmonellosis. Since Typhi and Paratyphi serovars do not infect other animals, most of what we know about adaptive immunity to Salmonella comes from infection of mouse strains with NTS strains. In this application we will use a new mouse model that is permissive for Typhi infection and allows side-by-side analysis of typhoidal and non-typhoidal disease. We propose to, (i) validate this new model by testing whether typhoid strains have delayed T cell and B cell activation in vivo, and (ii) determine whether ViCPS expression allows evasion of adaptive immunity.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

ABSTRACT Millions of Americans each year experience adhesion-related small bowel obstruction (aSBO), a condition associated with significant morbidity and prolonged hospitalization. Adhesions formed after previous abdominopelvic surgery can cause twisting of the bowel resulting in injury and a cascade of inflammation that results in progressive bowel wall edema with narrowing of the bowel lumen. This can lead to or worsen the bowel obstruction. Evidence from both clinical practice and animal models suggests that reversing this inflammation can hasten the return of bowel function and avoid surgery for people with aSBO. For example, intravenous dexamethasone is effective in avoiding surgery in patients with a form of SBO related to malignancy (malignant ascites or metastatic disease). A Cochrane review evaluated three RCTs and found “evidence that dexamethasone…may bring about the resolution of bowel obstruction”. An underappreciated aspect of these RCTs is that almost all patients had a history of abdominopelvic surgery. Since it is difficult to distinguish the extent to which an SBO is caused by adhesions from prior surgery or mass effect related to malignant ascites or metastases, we hypothesize that dexamethasone may be efficacious in resolving aSBO as well. The proposed, Comparison of Outcomes of Management of Bowel Obstruction (COMBO) trial is a double-blinded randomized study of a short course of dexamethasone + supportive care vs. placebo + supportive care. The primary outcome is non-operative resolution of aSBO without major complications as defined using modified National Surgical Quality Improvement Program (NSQIP) criteria. Secondary outcomes–clinical, healthcare utilization and patient- reported outcomes–will be compared overall and across subgroups (e.g., based on severity of aSBO, number of prior aSBO events, sex). Reducing inflammation with dexamethasone–a readily available and safe intervention–may improve the likelihood of non-operative management of aSBO and could change the management of millions of patients with this condition.

NIGMS - National Institute of General Medical Sciences

Project Summary The long-term goal of our lab is to understand the fundamental mechanisms by which RNA structures and RNA modifications can help cells distinguish between "self" and "non-self" molecules. One of these potent non-self molecules is double-stranded RNA (dsRNA), a particular structure of RNA that is not present at high levels in unstressed cells, but can be seen as a hallmark of viral infection. Unfortunately, transcription of endogenous repetitive elements within our own genomes can lead to the formation of dsRNA and activation of RNA sensors and inappropriate destructive cell signaling pathways even in the absence of infection. As such, the balance between sensing pathogenic dsRNA and tolerating self dsRNA must be finely tuned by negative regulators of RNA sensing. In addition, RNA sensing is also compartmentalized, with sensors in the cytoplasm kept away from the nucleus where RNA transcription takes place. Important for human health, loss of this balance in either direction is harmful, with negative regulator loss-of-function leading to inflammatory disease or autoimmunity while gain-of-function has been associated with cancer. Our research has shown that human viruses can actively prevent the formation of dsRNA by regulation of RNA splicing and removal of complementary introns. However, perturbation of viral splicing efficiency leads to production of nuclear dsRNA that is sensed by cytoplasmic sensors that subsequently move to the nucleus. This tool provides a unique opportunity to assess how cells respond to dsRNA derived from the nuclear compartment, and how tolerance of this non-self molecule can be broken. This proposal will explore the basic biological principles governing the interactions between nuclear dsRNA, RNA processing, and cytoplasmic RNA sensors. We will ask fundamental questions about how RNA structures, including intramolecular hairpins and intermolecular two-stranded helices, influence RNA sensor activation and the interplay between redundant sensing pathways. Additionally, we will investigate whether nuclear dsRNA carries specific chemical modifications that modulate its structure, recognition by sensors, or sensor activity. Finally, we will determine RNA binding proteins that specifically bind or regulate nuclear dsRNA using quantitative proteomics. The results will shed light on how healthy cells prevent inappropriate activation of RNA sensing responses to self-derived RNA. We will also learn how stressful situations, such as viral infection, can rewire existing signaling pathways to allow nucleic acid surveillance of the nucleus. The completion of this project will ultimately lead to a greater mechanistic understanding of nucleic acid sensing in cellular health and homeostasis.

EDF 13-14 Local

Compass Group Capital

NSF

Imagine doing some everyday activity, such as walking down a street to meet a friend at a restaurant. As you do this, your eyes are constantly moving—darting from your phone to street signs to the people and cars around you. Yet, despite what should be a jittery visual mess, we perceive a relatively smooth and stable visual world. For decades, scientists have been theorizing about how the brain creates this illusion of visual stability—recent advances in AI suggest an answer that can finally help crack this human perceptual code. The latest AI-powered vision-language models are becoming very good at recognizing visual objects and understanding scenes, even imagining what should be there and filling in missing parts much like the human brain does. This begs the question of whether these models are making sense of the visual world the same as humans. This project puts these new AI models to the test by having them generate plausible visual scenes, in real time, using only the few input samples that correspond to where a person looked while freely viewing the scene. This person is then shown either the real or AI-generated scene and asked if it is the scene that they just viewed. By identifying generated scenes that people cannot tell from real, cognitive scientists learn more about the semantic variability that objects viewed in peripheral vision might take while still seeming plausible (i.e., stable), and computational neuroscientists learn more about the algorithms underlying human visual stability and scene perception. This knowledge may also contribute to the development of smarter AI systems capable of perceiving the world more like humans do, thereby improving performance in time-critical applications such as self-driving cars and enhancing user experiences in augmented reality contexts. 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.

National Institutes of Health

Competing Revisions to Existing NIH Single Project Research Grants and Cooperative Agreements (Clinical Trial Optional)

NSF

Humans use memories of the past to figure out where to pay attention and what is most relevant to reach their current goals. For example, when driving to work, an individual can use their memory for specific streets to direct their attention to intersections that they know are tricky or dangerous. This process of “memory-guided attention” helps individuals behave efficiently and accurately even if they are in a rush. Memories, however, can be a double-edged sword. Because many street intersections can look similar to one another, confusing one intersection for another can lead to costly mistakes. This project aims to determine how the brain enables humans to minimize confusion between similar memories to direct their attention accurately and precisely. Understanding how memories are used for rapid decisions about where and how to pay attention has implications for education and artificial intelligence models. For educational settings, the project has potential to inform how students can be taught to avoid confusing similar memories of related problems and concepts, which could help students pay attention in the right way at the right time. More broadly, understanding how the brain solves this problem could inspire new ways that artificial intelligence models can be changed to avoid confusing memories for similar events, and to predict human attention more accurately. In addition to the research, this project includes research training and mentoring for high school, undergraduate, and graduate students in cognitive neuroscience. This project’s main focus is to determine how the brain’s memory systems help prevent competition, and promote cooperation, between memories to guide attention. This project focuses on a key brain region that is critical for building new memories and retrieving old ones: the hippocampus. The main prediction is that the hippocampus helps minimize confusion between similar memories by forming differentiated neural representations of them over time, and that this process helps prevent errors in memory-guided attention. This prediction is tested in using multiple methods: functional magnetic resonance imaging, eye tracking, measures of behavioral accuracy and response times, and sophisticated statistical models of brain activity and behavior. The project focuses on memories at different timescales. Aim 1 focuses on memories that were acquired some time ago and retained in long-term memory. Aim 2 examines interactions between these long-term memories and working memories acquired several seconds in the past. In Aim 1, the goal is to determine how the hippocampus prevents similar long-term memories from competing to guide attention. It tests the hypothesis that competition is initially overcome by brain systems involved in effortful control of behavior, with the hippocampus taking over to guide attention with additional experience. In Aim 2, the goal is to determine how working memories and long-term memories may be represented distinctly in the brain and over time in behavior to prevent them from competing with each other and helping them cooperate instead. Together, the overall goal is to uncover the powerful ways that the mind and brain minimize competition and promote cooperation between memories to influence attention. 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.

Education Department

The Department of Education (ED) announces the opportunity to apply for competitive grants for the Fiscal Year (FY) 2026 for the Braille Training Program, Assistance Listing Number (ALN) 84.235E.

Education Department

The Department of Education (ED) announces the opportunity to apply for competitive grants for the Fiscal Year (FY) 2026 for State Technical Assistance Projects to Improve Services and Results for DeafBlind Children (State DeafBlind Projects), Assistance Listing Number (ALN) 84.326T.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY/ABSTRACT Therapeutic strategies to halt antibody-mediated rejection (AMR) following lung transplantation are lacking, due in large part to the complex pathophysiology of the immune process and the multi-faceted approach that must be taken to establish a defined diagnosis. It is becoming increasingly clear that AMR has many endotypes, with donor-specific antibodies mediating a host of complement dependent and independent functions. Thus, the development of strategies to stratify patients based upon endotype has the potential to revolutionize the treatment of AMR. Pre-clinically, fluorescence imaging has been used to investigate a wide array of diseases and disorders. In transplantation, the focus has primarily been T cell-mediated rejection, detecting leukocyte trafficking to the graft via phagocyte-specific approaches or fluorogenic probes for inflammatory signatures, such as cathepsin B. In our own previous work, we developed a fluorogenic probe specific to granzyme B and reported its utility in monitoring therapeutic intervention in a murine model of myocarditis, a surrogate for cardiac transplant rejection. As such, there is a great unmet need to develop agents capable of non-invasively diagnosing or monitoring AMR. To this end, we have developed novel fluorogenic probes adept at detecting complement activation in real time, via the examination of complement convertase activity, as opposed to deposition products such as C4d, which persist for weeks at the site of deposition and can only be confirmed by invasive biopsy procedures. Thus, the goals of this proposal are to develop non- or minimally invasive techniques to image ongoing complement activation in-vivo. To accomplish this, we will use murine models of transplant rejection in concert with an assortment of complement inhibitors that act at different points in the complement activation pathway to characterize the extent to which these probes can determine complement activation. We will concomitantly examine their efficacy in a novel porcine ex-vivo perfusion system in which human complement activation can be modeled to investigate the potential clinical applicability in the setting of lung transplantation. To accomplish these goals, we propose the following specific aims: Aim 1: Examination of the extent to which fluorogenic convertase imaging can characterize AMR endotype, and Aim 2: Investigation of the translatability of convertase imaging to the stratification of AMR patients. On the completion of these studies, we will have validated a cadre of novel protease activatable complement specific imaging agents for use in the examination of AMR. We will have further dissected the significance of complement pathway specific proteins in mediating and modulating AMR. By using rodent analogues of clinically available FDA complement inhibitors, should our studies prove efficacious, our results could be rapidly translated.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Hospital-acquired pneumonia caused by multidrug-resistant Klebsiella pneumoniae (KP) poses a significant challenge in clinical settings due to limited therapeutic options. Immunotherapy has emerged as a promising strategy against such infections. To inform the development of immunomodulatory therapies to target this pathogen, it is crucial to understand the specific interactions between the immune system and multidrug-resistant KP. The complement system is one of the first lines of defense against bacterial infection. The canonical mechanism by which KP evades complement-mediated killing is through prevention of complement deposition either by modifying its capsule composition to prevent complement deposition or producing more capsule to cover potential complement binding sites on the bacterial membrane. There have been reports, however, of clinical KP isolates that are able to evade complement-mediated lysis despite high levels of complement deposition. The clinical isolates reported to demonstrate this phenomenon belong to the sequence type 258 (ST258). KP ST258 is an epidemic lineage that has caused numerous outbreaks in hospitals around the world. The KP ST258 lineage has diverged into two clades, Clade 1 and Clade 2, that differ primarily in their capsule locus. Clade 2 isolates are found much more frequently in infections than Clade 1 isolates, suggesting that they are more successful pathogens. Notably, in preliminary studies, Clade 2 isolates were found to both bind more C3 complement protein and be more resistant to serum-mediated killing than Clade 1 isolates. This proposal will explore a novel mechanism used by KP to evade complement-mediated killing despite C3 deposition, and will examine if this mechanism results in increased lung injury. Aim 1 will utilize in vitro assays, comparative genomics, and genetic approaches to investigate the requirement for the KP ST258 Clade 2 capsule in this new mechanism of complement-mediated killing. Aim 2 will utilize an in vivo murine model of pneumonia to investigate whether increased complement activation also increases lung injury, and if this can be mitigated through blockade of complement anaphylatoxins. Overall, this proposal will provide new insights into a novel mechanism of complement evasion and will pave the way for the development of targeted immunotherapeutic interventions for pneumonia caused by multidrug-resistant KP. Completion of the proposed training plan under the mentorship of Dr. Daria Van Tyne and Dr. John Alcorn will enable the applicant to develop and refine a wide variety of technical, intellectual, and professional skills that will be instrumental in her future success as an independent investigator and physician scientist.

NIAID - National Institute of Allergy and Infectious Diseases

Summary Mitochondria are released by dying neutrophils in peripheral blood and tissue, contributing to inflammation and organ damage. Little is known about mechanisms to clear the extracellular mitochondria. Neutrophils can generate, and release, complement C3, an important opsonin in removal of cell debris. However, whether neutrophils can proteolytically activate C3, and the role of C3 in clearance of mitochondria is not known. The aim of the present study is to explore mechanisms of mitochondrial clearance, with a focus on the role of neutrophils in proteolytically opsonizing mitochondria with complement C3b, and consequences of C3b in downstream clearance of mitochondria by myeloid cells. The premise is that neutrophils, through proteolytical cleavage, opsonize mitochondria with C3b facilitating their clearance while limiting inflammation and tissue damage. To investigate this, we have two main aims. The first aim investigates mechanisms related to complement C3 release and proteolytic cleavage by neutrophils. Neutrophils from patients (n=40) and controls (n=20) will be analyzed for C3 content by qPCR and flow cytometry. The identify of the C3-cleaving protease(s) will be identified using select protease inhibitors in neutrophils, supernatants and isolated NETs. Binding of C3 to mitochondria will be characterized using immunoprecipitation, mass spectrometry, and fluorescence microscopy. The second aim investigates the role of complement C3 in mitochondrial clearance, both in vitro and in vivo. In vitro, the role of C3 in opsonizing mitochondria will be determined in myeloid cells assessing uptake, induction of inflammatory cytokines, as well as NET formation by neutrophils. In vivo, GFP- tagged mitochondria will be injected in WT or C3-/- mice and assessed for biodistribution over time using confocal microscopy. At the completion of this proposed research, our expected outcomes are to have identified novel mechanisms regulating complement C3 release and acitvation by neutrophils. Further, we anticipate to have identified key pathways involved in mitochondrial clearance, and its implication for downstream effector functions in recipient cells. We expect this work to have a positive impact because it will offer novel insight into basic neutrophil biology, as well as identify targetable pathways to limit mitochondrial- mediated inflammation and subsequent organ damage in SLE.

NSF

This research seeks to understand the economics of supply chains where complementary suppliers may have market power. The objectives of this research are to evaluate the economic efficiency of the U.S. coal supply chain over the last thirty years, accounting for complementarities and market power, and to understand how efficiencies might have been impacted by changes in supplier market structure (e.g. mergers between coal suppliers), changes in the competitiveness of coal (e.g. after the U.S. natural gas boom), and the deregulation of wholesale electricity markets. These are important questions to address for this major industry. In this research, methods are developed that also could be applied in other industries. The research effort includes training of Ph.D. students, coordination of activities across schools at a land grant public university, and the presentation of the results to a wide range of stakeholders. The research involves three related projects that are made possible by combining confidential data on railroad shipments and power plant purchases of coal and transportation. Project 1 uses reduced-form econometric techniques to describe how shocks to electricity demand, shocks to electricity generating costs, and upstream shocks to the mining and railroad industries feed through into input prices and quantities. The results are interpreted through the lens of a theoretical models based on Cournot (1838) and Spulber (2017), which identify the possible effects of input complementarity with market power. Project 2 develops and estimates a static structural model of the supply chain and power plant output decisions. This model quantifies how supplier and downstream market power has varied over time and across space, and investigates the implications for counterfactuals (e.g., the introduction and elimination of subsidies for non-fossil fuel production or industry consolidation). Project 3 introduces dynamics into the model, testing whether prices are shaped partly by parties trying to anticipate and affect future changes in market structure (e.g., delay coal plant retirements) and, if so, estimating the effects on stylized counterfactuals, building on recent theoretical literature studying the effects of procurement on endogenous market structure. 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

Indicator species are often used to reveal trends and trophic “hotspots” for fishery and marine food web monitoring and can be particularly useful in the remote Southern Ocean due to the cost and accessibility of ship-based marine research. Biologging, the use of micro-electronic animal borne devices, is increasingly being applied to detect areas of species abundance and diversity and can be important for management efforts. An essential component to effective utilization of biologging is ground-truthing of the patterns, to establish the robustness of the data and the conclusions being drawn from it. This project aims to use at sea survey data and biologging data collected on marine mammals and sea birds in the Ross Sea to validate and refine how biologging information can predict indicator species distributions and identify areas of importance for biodiversity. Antarctic marine conservation strategies have focused on the identification and protection of bird/animal breeding colonies through national and international initiatives. However, foraging areas are also important, and ecosystem-based management involves establishing protected ocean areas where fishing is either excluded or tightly controlled. Seabird and marine mammal prevalence and distribution are often used as ecological indicators reflecting stability, change and spatial patterns in marine food webs. These patterns can signal “hotspots” of prey availability at scales from localized prey aggregations to broader oceanographic features such as fronts and upwelling plumes. At-sea surveys of seabird and marine mammal distributions have traditionally served to inform these decisions, but more recently telemetry tracking of individuals is being applied to the process. While biologging is a promising strategy, it is potentially a biased view due to the small sample size, being primarily focused on breeding adults, and limited to animals that are accessible to researchers (spatial bias). This project aims to ground-truth biologging data with at-sea data to better understand how well biologging describes the entire population, which will help to improve the effectiveness of Southern Ocean conservation and management. 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.

DECD

Complete a pedestrian walkway and install lighting in the green area

OPM

Complete an Economic Development Study for the Thompsonville section of Enfield.

Verde

Complete enhanced GPS-based Topography Assessment