Johns Hopkins University

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Heart failure with preserved ejection fraction (HFpEF) is the predominant form of heart failure and its incidence continues to rise. HFpEF disproportionately affects women after menopause and has a high mortality rate. Due to the lack of well-characterized mechanisms and targeted therapy, treatment of this underappreciated disease remains focused on symptoms and does not address the underlying structural changes of cardiac remodeling that are key to disease progression. I propose to identify the mechanisms underlying the primary structural cardiac changes that occur in HFpEF in a sex specific manner. Specifically, in this study, I propose that Thrombospondin-1 (TSP-1) is an attractive target in cardiac remodeling noted in HFpEF. Mechanistically, myocardial TGF-β activation is a common element in HFpEF. However, TGF-β inhibition is impractical due to the associated toxicity, necessitating the search for other options to influence this pathway. TSP-1 is a matricellular protein that has no structural role, but modulates cell-cell and cell-matrix interactions by interacting with growth factors and surface receptors. Moreover, it is induced in metabolic syndrome, activates TGF-β1, and inhibits metalloproteinase activity in the heart, which could modulate fibrotic pathways. My central hypothesis is that is that TSP-1 is a key matricellular protein and local mediator of TGF-β1-induced cardiac fibrosis whose expression and activation in cardiac fibroblasts is modified by sex hormones, resulting in augmented collagen deposition and crosslinking. I will investigate the effect of biological sex on TSP-1 activation, TGF-β signaling, and subsequent dysregulation of cell behavior, tissue mechanics, and ventricular function. I will also determine the therapeutic potential of targeting TSP-1 in a rodent model of HFpEF. In Aim 1, my goal is to determine the regulatory mechanisms of TSP-1 and downstream consequences of TSP-1 induction in cardiac fibroblasts. Using human cardiac fibroblasts cells, I will identify the mechanisms by which hypoxia and hyperglycemia induce TSP-1, which then activates TGF-β1 and fibrosis. In Aim 2, my goal is to determine if a gain of androgen signaling boosts TSP-1 expression. Using human cardiac fibroblasts, we will describe the relative gain of androgen signaling post-menopause TSP-1 levels in relation to TGF-β activation. In Aim 3, my goal is to establish TSP-1 as a targetable enzyme in HFpEF. Using an in vivo rat model of HFpEF we will test if TSP-1 inhibition prevents or reverses HFpEF ex vivo and in vivo. This study will establish 1) the therapeutic potential for TSP-1 inhibition in HFpEF, 2) that ratio of estrogen to androgen modifies cardiac remodeling as opposed to absolute hormone levels, and 3) introduce a new therapeutic approach and a new target to treat HFpEF by addressing matrix remodeling. In addition, completion of this project will allow me to align my clinical expertise as a cardiac anesthesiologist with my research focus and fully transition me to an independent investigator.

NIH Research Projects · FY 2024 · 2024-09

Abstract Homicide, often at the hands of intimate partners, is a leading cause of pregnancy-related death. Intimate partner violence (IPV) is a widespread and serious public health problem. Globally, 30% of ever- partnered women experience physical or sexual IPV, and over one third of female homicides are perpetrated by intimate partners. Significant evidence demonstrates that IPV is a preventable cause of maternal mortality, and poor health before, during, and after pregnancy, including severe maternal morbidity, especially for populations that are disproportionately affected by maternal mortality and severe morbidity. The evidence base on IPV has yet to translate evidence into effective interventions to improve maternal health and safety and promote health equity. A core competency for maternal health researchers is understanding how to best measure IPV and conduct IPV-related research in accordance with ethical protections specific to this topic. These skills are critical building blocks to integrate IPV concepts within clinical, epidemiological, and intervention research and practice in maternal health. Yet to date, dedicated IPV-related coursework in health- related graduate and professional programs is quite limited. IPV is often included only peripherally within coursework, and does not cover the nuances of measurement across populations, necessary ethical protections, and importantly, the culturally-specific assessments and interventions necessary for successful implementation and impact to achieve health equity. IPV-related training is thus an actionable gap in our national ability to understand and address IPV as a threat to maternal health and health equity. Our experienced, multidisciplinary team thus proposes a 2-year training project to: 1) develop an applied educational curriculum to advance IPV measurement and research skills for diverse populations, 2) pilot and implement the curriculum through an online accelerated short course within the Johns Hopkins University Institute series, and 3) accelerate IPV research skills application by fostering community among trainees, and providing ongoing mentoring and technical support as they build and apply their new skills. Our project fills a critical gap in available training and accelerates progress on national goals of improved maternal health and pregnancy outcomes through equipping the clinical and research workforce with specific skills and knowledge necessary to integrate IPV-related experiences within maternal health research. The training will accelerate the quality and impact of IPV-related clinical and intervention-related maternal health research for populations in greatest need. In doing so, we advance national capacity to mitigate preventable maternal mortality, decrease severe maternal morbidity, and promote health equity.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Premenstrual dysphoric disorder (PMDD) is a severe affective disorder impacting millions of women worldwide, thought to be due to impaired sensitivity to hormone fluctuations across the menstrual cycle. Low-dose selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for PMDD, but their mechanism in PMDD is poorly understood. Despite this morbidity and limited treatment options, research on PMDD’s pathophysiology and treatment lags behind that of other brain disorders. A potential aspect of PMDD’s pathophysiology is altered interaction between steroid hormones - specifically gamma-aminobutyric acid (GABA)ergic neuroactive steroids (NAS) - and their target, the GABA-A receptor (GABA-A-R). GABAergic NAS, such as the progesterone metabolite allopregnanolone, fluctuate across the menstrual cycle and are associated with luteal phase symptom emergence in PMDD. The proposed study will examine three aspects of GABAergic function in PMDD, to clarify its pathophysiology: 1) GABAergic NAS fluctuations, particularly allopregnanolone (ALLO) and its isomers, 2) GABA-A-R subunit expression, and 3) GABAergic neurosteroidogenic enzyme expression. A key focus of this placebo-controlled trial is to assess how these parameters are affected by low-dose SSRI treatment in women with PMDD, shedding light on treatment mechanism. In this multi-site study, we will assess 288 women with regular menstrual cycles (72 controls, 216 with PMDD), across the luteal phase of the menstrual cycle. In a second luteal phase, women with PMDD will be randomized to sertraline or placebo. We will capture three outcome measures: 1) plasma NAS changes within subjects at multiple timepoints across the luteal phase using precise gas chromatography/mass spectrometry (GC/MS) methods, 2) GABA-A-R subunit expression across the luteal phase in blood cells measured via real-time polymerase chain reaction (RT-qPCR), and 3) GABAergic neurosteroidogenic enzyme expression. We will compare controls versus women with PMDD, and within those with PMDD compare sertraline versus placebo. The study explores a mechanistic hypothesis about NAS dynamics and GABA-A-R plasticity in women with PMDD, and focuses on biologically relevant treatment target engagement. The multiple investigators bring complementary expertise; Drs. Hantsoo and Payne in prospective studies of reproductive affective disorders, and Dr. Pinna in applying state-of-the-art methods to study the impact of NAS on GABA-A-R function. This study represents a critical step in elucidating NAS and GABA-A-R dynamics in women with PMDD when treated with low-dose SSRIs, which may shed light on both pathophysiology and treatment response mechanisms. Understanding PMDD’s pathophysiology may also inform treatment development, i.e.GABA-modulating drugs that have recently emerged as treatments for postpartum depression. Assessing parameters affected by SSRI in PMDD could lead to developing a personalized medicine approach.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Patients with advanced acral melanoma (AM) suffer worse outcomes relative to patients with cutaneous melanoma (CM), in part, because they do not respond as well to treatments approved for CM including immune checkpoint blockade and BRAFV600E inhibitor strategies. Tailored therapies are warranted for patients with advanced AM given that AMs differ from CMs in a) cell of origin (volar melanocytes versus non-volar melanocytes, respectively) and b) mutational frequencies in targetable driver genes (e.g., BRAF hotspot mutations in 18% of AMs versus 46% of CMs). In this application, we focus on the unique biological dynamics induced by the plantar skin microenvironment of the foot where AMs most commonly arise in. The plantar microenvironment is mechanically stiffer relative to non-plantar skin sites (e.g., arm) where CMs arise, and the resident dermal fibroblasts in plantar skin display cancer associated fibroblast (CAF)-like markers in the absence of cancer cells. In the first aim, we will mechanistically define how matrix stiffness impacts AM metabolism. Our preliminary data identify elevated lysosome catabolism and collagen degradation gene signatures in AM cells grown in the stiffer plantar skin of the foot versus softer non-plantar skin of the flank in mice. We will track changes in lysosomal catabolism in a panel of in vitro and in vivo AM model systems using a) live cell reporters (e.g., mCherry-eGFP-LC3), b) Western blotting of protein markers of lysosome activity (e.g., LC3B, p62, NBR1), and c) bulk and single cell RNA sequencing analyses. In the second aim, we are testing the hypothesis that matrix stiffness-induced lysosomal catabolism promotes metastasis to the liver and insensitivity to CDK4/6 inhibitor therapy. These studies will not only determine whether liver metastasis and therapy resistance emerge via elevated lysosomal catabolism, but will also provide us with information on the relationship between matrix stiffness and lysosomal catabolism that will extend to other tumor types including breast and pancreatic where tissue stiffening is associated with poorer survival. In the third aim, we are testing the hypothesis that plantar fibroblasts promote AM metastasis and therapy resistance through the secretion of factors including matrix gla protein (MGP). We expect that targeting separate aspects of the plantar skin microenvironment in a rationally designed way (in vitro and then in preclinical in vivo models) will enable the reduction of resistance onset and metastatic disease in patients.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY South Africa continues to shoulder the highest burden of people living with HIV (PLHIV) in the world. In an effort to minimize the national burden of the HIV epidemic, South Africa has been at the forefront of adopting biomedical prevention. Still there is work to be done, as key populations (vulnerable patients, young men and women) are still not accessing lifesaving preventative and therapeutic HIV services. The ED provides care to high volumes of adults who may not otherwise interact with the health system, and thus is an important testing and linkage to care venue. A Universal Test-and-Connect (UTC) strategy promotes access to both preventative (pre- and post-exposure prophylaxis) and therapeutic (ART initiation) HIV services from the ED. It can expand care to otherwise missed populations and aligns directly with a differentiated service delivery model that is integrated within existing, sustainable service delivery venues. This status neutral approach has the ability to normalize HIV services in a venue that is untouched but shows great promise. The goal of this R34 proposal is to integrate UTC in two high volume EDs (one a high-volume tertiary care trauma center and another a high-volume district level facility) in Cape Town, South Africa. We first aim to integrate HIV assessment over a period of one year into routine care to define the prevalence and key characteristics of ED patients eligible for UTC interventions (Aim 1). We then seek to pilot (N=100) the delivery of oral and long-acting pre-exposure prophylaxis (PrEP) to ED patients (Aim 2). This has never been trialed before in the ED context in South Africa, and we seek to determine the preliminary uptake of PrEP (oral and long acting) in ED patients, as well as PrEP continuation at six weeks. Lastly, we propose to determine the operational feasibility of UTC using value stream mapping to map patients journeys in the ED and determine healthcare worker acceptability using the normalization process theory framework to guide physician and nursing surveys (N=160) and in-depth interviews (N=40). This new collaboration between Johns Hopkins University and the Desmond Tutu HIV Foundation brings together our complementary expertise in ED-based HIV service delivery and action research to reach missed populations. Together we seek to deliver the ED as an untapped partner in the fight against HIV, so that all populations can access life changing preventative and therapeutic HIV services.

NIH Research Projects · FY 2025 · 2024-09

Evidence from human epidemiological studies and animal models reveals that chronic psychological stress influences the evolution, dissemination, and treatment results of neoplasia. Chronic stress is transduced into a physiological signal primarily via the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). Within the brain, corticotrophin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (PVNCRH neurons) integrate incoming sensory information and trigger glucocorticoid (GC) release from the adrenal gland. These neurons also promote the release of the adrenergic neurotransmitter norepinephrine (NE) throughout the body via the SNS. This positions PVNCRH neurons as central players in both the sensation and systemic response to stress. Cancer patients undoubtedly experience chronic stress (e.g., prognosis-related), and this stress is strongly linked to an increased risk of metastasis/recurrence. Yet, how stress promotes metastasis is poorly understood. Closing this knowledge gap is challenging given the involvement of multiple organ systems and the need to bridge different scientific disciplines. We assembled an interdisciplinary team to elucidate the mechanisms connecting stress and metastasis. By introducing chronic stress protocols in mouse models of metastatic breast and pancreatic cancer, we uncovered that HPA-axis-driven GC release triggers neutrophil extracellular trap (NET) formation, which is crucial for stress-induced micro-metastasis establishment from disseminated cancer cells. Furthermore, we detected stress-induced SNS activation at the metastatic site. Notably, chronic stress also caused resistance to immune checkpoint blockade (ICB), likely via the actions of both GCs and NE. Finally, we found that the presence of metastasizing cancer itself hyperactivates PVNCRH neurons. Thus, our findings establish a maladaptive stress-metastasis feedforward loop involving the HPA axis, SNS, and immune system: stress ► PVNCRH neuron activation ► SNS & HPA-axis activation ► metastasis progression ► PVNCRH neuron hyperactivation. Here, we propose to investigate how stress impacts metastasis and ICB responses, and how metastasis, in turn, drives the activity of this feedforward loop. In Aim 1, we will address how GCs cause NET formation and how NETs promote metastasis. In Aim 2, we will determine how the SNS influences the response to ICB therapy, employing a novel technique to manipulate the sympathetic nerves that innervate metastases. Additionally, we will test if adrenergic receptor blockers improve ICB treatment responses in mice exposed to stress. In Aim 3, we will address how metastases changes the electrophysiological properties of PVNCRH neurons, allowing us to identify putative ion channel families altered by metastatic cancer. Our studies will provide mechanistic insights into the maladaptive stress-metastasis feedforward loop and have implications for preventing metastasis from disseminated cancer cells and for treating stage IV cancer. Moreover, we are breaking new ground by showing that the communication between cancer and the brain is bidirectional.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY / ABSTRACT Pulmonary arterial hypertension (PAH) is a progressive and incurable condition, with a median survival of less than 10 years. Right ventricle (RV) adaptation to increased pulmonary artery (PA) pressures is a crucial factor in determining disease outcomes. However, metrics of RV function remain absent from many clinical risk scores, highlighting a need to determine the best way to measure RV function. By measuring the ratio of RV contractility to afterload, RV-PA coupling represents a metric which can quantify the RV adaptive response. RV-PA coupling has demonstrated utility as a high-fidelity predictor of clinical outcomes but is not routinely measured in clinical practice due to its resource-intensive nature. Thus, there is an urgent need to identify accessible metrics that can serve as surrogates for RV-PA coupling and report on RV adaptation. In this proposed work, we hypothesize that a set of clinically available metrics can be identified as surrogates for RV-PA coupling and can improve survival predictions of existing clinical risk scores. We have access to data from over 100 subjects followed for up to 10 years who underwent same-day right heart catheterization (RHC), RV pressure-volume (PV) loop analysis, cardiac MRI (CMR), and transthoracic echocardiogram (TTE) at a single center after referral for suspected PAH. Leveraging this unique dataset, our proposed research aims to 1) identify a set of clinically available metrics using a multivariable model which can act as surrogates for RV-PA coupling and indicators of RV adaptation. We will 2) evaluate the association between the metrics from this model and transplant-free survival in our single-center cohort. We will then 3) externally validate survival predictions in a multi-center cohort and determine if these metrics improve prognostic value when added into the widely used clinical risk score, the REVEAL Lite 2.0. In conclusion, the proposed study aims to demonstrate that clinically accessible metrics can serve as surrogates for RV-PA coupling and indicators of RV adaptation. In identifying these metrics, this work has the potential to improve survival predictions and our assessment of disease progression in PAH. This research will provide valuable research skills in clinical study design, prediction model development, and longitudinal analysis. The proposed work will serve as an exceptional opportunity for developing the fundamental skills and generating the preliminary data for a future K-level Career Development Award.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY This K99/R00 application details career development and research plans that have been uniquely tailored to facilitate the transition of the principal investigator, Dr. Cristina Santarossa, to an independent academic position. The K99 research program aims to characterize the cellular function of Escherichia coli LetA, a lipid transporter that is conserved across Gram-negative bacteria and certain eukaryotic parasites. The K99 phase involves a strategic career development plan, overseen by a team of multi-disciplinary mentors and collaborators, that will allow Cristina to gain essential training in microbiology and lipidomics and acquire important career skills such as lab management, mentoring, grant writing, and science communication. The plan also includes clear and actionable steps for identifying and successfully obtaining an independent tenure-track faculty position by the end of the K99 phase. The R00 research program then aims to determine the structure and function of LetA proteins that structurally diverged from E. coli LetA. Core research questions include: How can these structural variants facilitate lipid transport? What substrates may they be transporting? What is their cellular role? To address these questions, Cristina has developed a comprehensive research plan that involves identifying the cellular substrates of E. coli LetA and two structural variants from K. pneumoniae and P. falciparum, and structural determination of the LetA structural variants and cellular assays to probe their function. This research will provide key insights into the physiological role of a new mechanism of lipid transport that is likely conserved. The proposed studies will largely take place at Johns Hopkins University, which is home to a vibrant and collegial community of microbiologists, cell biologists, and biophysicists. This environment is ideal to facilitate the successful completion of Cristina’s K99 research program and Cristina’s goal of transitioning to a successful career in independent academic research.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT The introduction of the integrase strand transfer inhibitor (INSTI) class of HIV drugs transformed the treatment of persons with HIV (PWH), offering highly effective and well-tolerated options with fewer drug interactions. However, concerns about INSTIs causing weight gain, particularly in women, have been raised in various studies. Despite recent investigations, a definitive explanation for the mechanism behind INSTI-associated weight gain remains elusive. Recently, we reported that the administration of dolutegravir led to an increase in fat mass and body weight through suppression of thermogenic processes in a rodent model, which was associated with a disruption of mitochondrial respiration and reduced expression of uncoupling protein1 (UCP1) in adipose tissues. Moreover, other groups further confirmed these results using non-human primates (NHPs) infected with SIV. Interestingly, it has been well-documented that estrogen plays a critical role in promoting thermogenic processes through the peripheral and central nervous systems. Our preliminary data shows that dolutegravir inhibits estrogen signaling action, and genetic deletion of estrogen receptors in adipocytes attenuates dolutegravir- mediated suppression of the thermogenic process. Based on these observations, we hypothesize that dolutegravir reduces energy expenditure via disrupting estrogen action in adipocytes, leading to the weight gain associated with INSTIs. To further investigate this hypothesis, we will first define the molecular mechanisms by which INSTI-based ART disrupts whole-body metabolism and leads to weight gain via the estrogen receptor (ER) using a transgenic mouse model in which ER is genetically deleted in adipose tissues. We will perform biochemical and molecular analyses combined with multi-omics approaches, including single-cell RNA and ATAC-sequencing to further elucidate the molecular network associated with INSTI-related adipose function disruption via ER (Aim 1). Next, to address the absence of a chronic retroviral infection in a murine model, we will investigate how estrogen affects INSTI-based ART-mediated weight gain over time via disrupted thermogenesis in NHPs infected with SIV and ovariectomized with or without estrogen replacement. We will also perform temporal transcriptomic analyses on adipose tissues to gain a comprehensive understanding of how these tissues are altered through infection, ART initiation, and E2 manipulation over time (Aim 2). Finally, we will evaluate the effects of INSTI-based ART on thermogenic pathways and mitochondria functions in adipose tissue at multiple time points from PWH starting INSTI-based treatment and followed for one year. Moreover, we will perform integrative transcriptomics analyses utilizing cross-species omics data (Aim 3). These multidisciplinary and translational works will shed light on how INSTIs contribute to weight gain, especially in females, and inform the development of new strategies to reduce excess adiposity and metabolic dysfunction in PWH.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Neuronal tissue is the most energy consumptive tissue type of the entire body, and as such, depends heavily on the health and proper regulation of its mitochondria, its main source of energy. Thus, mitochondrial dysfunction is linked to a number of neuropsychiatric diseases, including the neurodevelopmental disorder Fragile X Syndrome (FXS). FXS is characterized by loss of the Fragile X Messenger Ribonucleoprotein (FMRP), an RNA- binding protein that has been shown to interact with microRNAs (miRNAs) and components of the RNA-induced silencing complex (RISC). Interestingly, using an optimized Ago-CLIP method that unambiguously identifies miRNA:target RNA interactions within the RISC, our lab has identified prevalent binding of miRNAs to mitochondrial transcripts (mt-RNA) in the mammalian forebrain. Though mitochondrial dysfunction in FXS has been identified, a connection with RISC and targeting of mt-RNA has not yet been explored. This proposal seeks to further characterize the molecular underpinnings of these observed miRNA:mt-RNA interactions, as well as their impact in both health and disease (FXS). Specific Aim 1 proposes to use the same optimized Ago-CLIP method, termed CIMERAseq, to determine the subcellular compartment in which the miRNA:mt-RNA interactions are occurring, as well as use a targeted approach to identify cell-type specificity of the transcript interactions. Specific Aim 2 explores the possible functional effect of the observed binding by altering levels of select miRNAs identified in our data and recording the effect in three ways: i) transcript abundance (via sequencing and qPCR) ii) protein abundance (via Western blot and BN-PAGE), and iii) mitochondrial function (via assessment of respiratory function, ATP synthesis, and reactive oxygen species (ROS) production). Aim 2 also uses the same effect readouts to investigate mitochondrial perturbations in a mouse model of FXS (Fmr1 KO). If successful, the proposed specific aims will aid in understanding the role of miRNAs as mitochondrial gene regulators in the mammalian forebrain, both in health and disease. In addition to completion of the proposed aims, this proposal outlines a training plan formulated specifically for my long-term goal of becoming a well- rounded independent scientist. Training received through the course of this fellowship will focus on enhancing my skills in molecular biology methods, bioinformatic methods, and scientific communication and writing. My sponsor and university, the Johns Hopkins University School of Medicine, are outstandingly equipped to not only allow for completion of the proposed experiments but also to provide the resources needed to receive exceptional training in the areas described. The Biochemistry, Cellular and Molecular Biology (BCMB) program in which I am enrolled is dedicated to providing an exceptional training environment and will support completion of the research plan as well as career training opportunities. This fellowship will support not only impactful research toward understanding miRNA and mitochondria in FXS pathology, but also my development into a capable and independent neuroscientist.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY HIV remains the leading cause of death among adults in South Africa despite the availability of antiretroviral therapy (ART) due to failure to initiate ART and failure to remain on ART. Among people living with HIV (PLWH) who are hospitalized, 17-26% die within 6 months of hospital discharge potentially contributing to more than half of all HIV-associated mortality in South Africa. There are heterogenous reasons for mortality that include missed diagnoses, psychosocial barriers to completing treatment plans, and structural barriers that include food insecurity. To respond to the complexity of underlying causes of mortality we developed and piloted a disease neutral intervention to reduce posthospitalization mortality: HomeLink. This intervention consisted of structured posthospitalization home care visits with psychosocial counselling and nutritional supplementation and reduced posthospitalization mortality by 60%. These results raise important questions regarding reproducibility and scale-up of this intervention. In order to inform policy, the most feasible and cost- effective elements need to be identified. Here we are proposing a fully powered study of a refined HomeLink2 intervention to compare usual care to structured home visits or home visits plus nutritional supplementation. In addition, we will identify underlying mechanisms of the intervention effectiveness including the impact on timeliness of acute care, medical diagnoses, adherence to ART (through viral load testing), and psychosocial metrics. We will further assess implementation outcomes to guide future refinement of intervention delivery. Finally, we will use findings from the randomized trial to complete costing and cost-effectiveness analyses to inform policy makers regarding cost of HomeLink2 and cost-effectiveness of home visits alone or home visits plus nutritional support to inform potential scale-up and long-term sustainability. This project has the potential to generate considerable new knowledge on interventions that could dramatically reduce HIV-associated mortality in South Africa and other low- and middle-income settings. This proposed study is very likely to generate actionable knowledge to improve outcomes for PLWH and contribute to overall goals of HIV epidemic control.

NIH Research Projects · FY 2025 · 2024-09

The goal of this study is to understand PrEP user choices, preferences, and implementation impact of the roll- out of long-acting injectable PrEP alongside oral PrEP among women in Malawi. As the roll-out of expanded PrEP options increases globally, there is growing excitement that this could accelerate progress towards ending HIV and provide discreet, user-controlled prevention options for women. Yet, real-world choices and switches between oral and injectable PrEP products have not been evaluated on a large-scale and high rates of product continuation are not guaranteed as has been demonstrated with oral PrEP use globally. Thus, it is critical to understand PrEP user patterns and outcomes of PrEP implementation early during the expansion phase of new biomedical technologies. The PathToScale is already funded – it is an implementation science study which is rolling out injectable PrEP in Malawi to 9,900 people in real-world conditions in January 2024, alongside further President's Emergency Plan for AIDS Relief supported allocations for oral PrEP. The proposed BetterInfo on PrEP study will leverage the PathToScale platform and critically extend work to evaluate use patterns, preferences, and decision-making among women discontinuing PrEP whose choices and outcomes will remain unknown in the absence of the proposed BetterInfo study. Specific Aim 1: Evaluate longitudinal patterns of oral and long-acting injectable PrEP use in women in Malawi and the impact of BetterInfo tracing approach on re-engagement in PrEP care. Specific Aim 2: Assess decision-making among injectable and oral PrEP users and providers, as well as preferences for implementation delivery and support. In-depth interviews with five sub-sets of PrEP user types traced (n=80) and healthcare providers/implementing partner stakeholders (n=16) will explore decision-making and implementation and behavioral facilitators and barriers to oral and injectable PrEP use guided by the theoretical domains framework and Capability, Opportunity, Motivation Behavior model. Further, a discrete choice experiment/best worst scaling will be conducted among the sub-sample of traced discontinued PrEP users who remain at high risk for HIV acquisition (n=~270) to better understand preferences around PrEP product choice, clinical support and re-engagement strategies. Specific Aim 3: Co-design strategies for optimizing PrEP continuation and re-engagement to achieve implementation impact for women in Malawi by combining scenario-modeling and human centered design workshops. This will be achieved by leveraging PathToScale and BetterInfo tracing data within mathematical models to estimate the comparative, community-level transmission impact of oral and injectable PrEP implementation strategies under different trajectories of PrEP use, and co-designing PrEP engagement and provider communication strategies through human centered design workshops with the community partnership council, Ministry of Health and implementing partners/providers and clients, factoring in data across aims.

NIH Research Projects · FY 2025 · 2024-09

Project Summary: For >18 years, Makerere and Johns Hopkins universities have partnered in Uganda to characterize the epidemiology of hepatitis B (HBV) and HIV co-infection, define the subsequent sequelae including hepatocellular carcinoma (HCC) and advance clinical management. Through an NCI-supported U54 program, we conducted one of the largest and well-characterized studies of HCC in Africa, recruiting from both central urban and northern rural regions of Uganda. Moreover, we have performed mixed-methods research to identify knowledge and clinical barriers to implementation of HBV screening and diagnosis within HIV care settings. Recently, our collaborative team successfully completed a demonstration project focused on integrating HBV diagnostic and treatment services into HIV care in the West Nile region and also launched an implementation assessment of antenatal care screening for and delivery of HepB birth dose vaccination at multiple sites across Uganda. Importantly, the burden and lethality of HCC can be successfully ameliorated with implementation of evidence- based and contextually appropriate prevention, screening, diagnostic and treatment interventions. However, these measures have not been comprehensively implemented into routine care settings in Uganda or other high HCC burden regions of sub-Saharan Africa. Leveraging this long-standing work in Uganda, our proposed bundle of interventions, the Liver Cancer Comprehensive Control (LC3) package, incorporates diagnostic testing and treatment of HBV, primary prevention through vaccination of susceptible adults, and referral for liver disease staging and active surveillance for early HCC detection among at-risk populations. We will integrate the LC3 package into existing HIV care delivery platforms among adults living with HIV in Uganda. Our overarching goal is to demonstrate the reach, effectiveness, and maintenance of delivering LC3 services within HIV care settings. Successful implementation of LC3 in Uganda will serve as a model for integrating complex cancer control intervention packages into existing HIV care delivery systems across similar countries in sub-Saharan Africa.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Recent clinical and preclinical studies have shown that seizures can adversely interact with brain tumors to sƟmulate tumor cell proliferaƟon and invasion. Moreover, posƟctal hypoperfusion can give rise to hypoxia-driven radiaƟon resistance and convenƟonal anƟ-seizure drugs can limit the efficacy of chemotherapeuƟc agents. CollecƟvely, these factors complicate the clinical management of these paƟents and degrade their quality of life (QOL). Therefore, an understanding of the physiology underlying the “seizure-brain tumor nexus” is crucial for treaƟng brain cancer paƟents and enhancing their QOL. However, brain tumor associated seizures occur at random, creaƟng a major obstacle for studying them with standard imaging technologies (e.g., fMRI/PET) which only offer a few hours of imaging. While EEG can circumvent this problem, it does not provide the spaƟal specificity required to parse the seizure-tumor nexus. AddiƟonally, most imaging technologies also require anesthesia, which confounds the assessment of seizure-induced hemodynamic (i.e. blood flow and oxygenaƟon) abnormaliƟes. These hurdles limit our ability to image the seizure-brain tumor nexus in vivo and elucidate the interacƟons between seizure-induced neuronal hyperexcitaƟons, posƟctal hypoxia, tumor cell proliferaƟon and mobilizaƟon. To address these issues, we propose to develop a new class of remotely controlled, cloud-based, mulƟcontrast miniaturized microscopes called “NeuroVu” for characterizing the seizure-brain tumor nexus without Ɵme constraints in unanestheƟzed or freely behaving animals. NeuroVu will be capable of real-Ɵme dual channel fluorescence (dual-FL), dual intrinsic opƟcal signal (dual-IOS) and laser speckle contrast (LSC) imaging to enable conƟnuous in vivo “neurosurveillance” by imaging both, the seizure-associated hyperexcited neurovascular unit and its interacƟons with proliferaƟng brain tumor cells. A variant of NeuroVu (NeuroVuopto) will be capable of optogeneƟc-based inhibiƟon of neuronal hyperexcitability to directly assess the impact of seizures on brain tumor invasion. QuanƟfying these dynamic interacƟons will provide invaluable insights into the seizure-brain tumor nexus, create a novel platiorm for developing synergisƟc anƟ-seizure and anƟ-cancer therapeuƟcs, and pave the way for more efficacious management of paƟents with brain cancer.

NSF Awards · FY 2024 · 2024-09

With the support of the Chemical Catalysis program in the Division of Chemistry, Professor V. Sara Thoi of Johns Hopkins University and Professor Fanglin Che of University of Massachusetts, Lowell are studying the design of catalytic materials for electrochemical synthesis of organonitrogen compounds. Organonitrogen species are a ubiquitous class of compounds used in a variety of industries, from agriculture to pharmaceuticals. Urea, for instance, is an important fertilizer, but it is industrially derived from a highly energy-intensive process called the Haber-Bosch process. Electrochemical transformation of abundant carbon and nitrogen molecules, such as carbon dioxide and nitrogen gas, to organonitrogen products thus emerges as an attractive approach. Electrochemical synthesis can be conducted at room temperature, ambient pressure, and in water. Moreover, the rise in renewably generated electricity provides a path towards decarbonization of the chemical manufacturing industry. This project uses a combination of computational and experimental chemistry to design, synthesize, and test new catalysts for forming commercially valuable organonitrogen compounds, such as urea, acetamide, and N-methylamines. The expected outcomes are the fundamental knowledge for activating small molecules to form carbon-nitrogen bonds, the identification of design parameters for synthesizing efficient catalysts, and the broader applications of electrochemical synthesis to a new class of commodity chemicals. Additionally, the educational goal of this project is to engage young students in the STEM field via the publicly accessible video series, “Meet the Chemist,” which highlights the unique and diverse paths of undergraduate students to chemical research. Moreover, a novel theory course on applied machine learning for computational catalysis will be developed for undergraduate and graduate students. The scientific and educational merits of this project advance the frontiers of chemical synthesis, promote public engagement between researchers and young students, and align with our national interest for decarbonization. With the support of the Chemical Catalysis program in the Division of Chemistry, Professor V. Sara Thoi of Johns Hopkins University and Professor Fanglin Che of University of Massachusetts, Lowell are studying the design of catalytic materials for electrochemical synthesis of organonitrogen compounds. This project will focus on a class of metal-organic materials called boron imidazolate frameworks (BIFs) for electrochemical C-N coupling to form commercially valuable products, such as urea, acetamide, and N-methylamines. Owing to their synthetic tunability, BIFs provide facile access to a range of isostructural metal-organic materials to identify structure-function relationships, serving as an ideal materials platform for fundamental insights to catalytic mechanisms. This project has three objectives: i) identify the structure-function relationships between the electronics of the BIFs and C-N coupling, ii) observe key intermediates via in situ vibrational spectroscopy, and iii) develop physics-informed machine learning to identify design criteria for new BIF catalysts. Together, this knowledge will be used to explore the scope of C-N coupling products, using inexpensive and abundant carbon and nitrogen precursors such as carbon dioxide, aldehyde, ketones, dinitrogen, nitrite, nitrates, and amines. Additionally, we will expand an existing video series, called “Meet the Chemist,” to highlight the unique and diverse paths of undergraduate students to chemical research. The videos, which are publicly available, are designed to encourage young students to learn that people of all backgrounds can engage in STEM research. Moreover, a novel theory course on applied machine learning for computational catalysis will be developed for undergraduate and graduate students. Along with these broader outreach goals, this project aims to enhance the utility of electrochemical synthesis for a wide range of industrially relevant compounds, thereby creating opportunities to decarbonize the chemical industry. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-09

This award funds research in macroeconomics and bounded rationality. The team starts with the observation that in the formalization of representativeness (Kahneman and Tversky, 1972) developed by Gennaioli and Shleifer (2010), overreaction and confidence are affected by uncertainty, as a news effect interacts with an uncertainty effect. In the time series domain, this interaction emerges in a smooth version of Diagnostic Expectations (DE). Under Smooth Diagnostic Expectations (Smooth DE), agents overreact to new information. Since new information typically changes not just the conditional mean, but also the conditional uncertainty, changes in uncertainty surrounding current and past beliefs affect the severity of the DE distortion and confidence. As a result, Smooth DE ends up connecting two vastly popular branches of Economics that have largely proceeded in parallel: the Diagnostic Expectations literature and the Uncertainty literature (Bloom, 2014). The research consists of three projects. In the first project, the team highlights the inherent link between representativeness and uncertainty and introduces Smooth DE as the natural time series formalization of such a link. Under Smooth DE, agents over-react to new information as captured by the change in the current distribution of future events with respect to a reference distribution. Changes in uncertainty surrounding current and past beliefs affect the extent of the DE distortion. Smooth DE implies a joint and parsimonious micro-foundation for key properties of survey data: (1) overreaction of conditional mean to news, (2) stronger overreaction for weaker signals and longer forecast horizons, and (3) overconfidence in subjective uncertainty. In the second project, the team studies quantitative business cycle models that leverage insights from the Smooth DE framework, as well as from the team’s previous work on DE, imperfect information, and non-linear solution methods. The goal is to provide a rigorous and parsimonious account of business cycle properties that emerges from a smooth DE model with signal extraction. An analytical RBC model featuring Smooth DE accounts for overreaction and overconfidence in surveys, as well as three salient properties of the business cycle: (1) asymmetry, (2) countercyclical micro volatility, and (3) countercyclical macro volatility. A negative shock that raises perceived uncertainty increases the over-reaction to both idiosyncratic and aggregate shocks, and deepens the contraction. This rich and novel propagation arises because the intensity of the DE distortion is state-dependent. In the third project, the team focuses on actionable implications. Under smooth DE, the severity of the DE distortion varies in response to the level of uncertainty faced by agents. The team uncovers a novel role for decision makers: by reducing uncertainty, decision makers can now reduce the severity of the DE distortion and thus stabilize agents’ psychological biases. Thus, a redistributive rules that reduce cross-sectional uncertainty could also be beneficial for macroeconomic stabilization. The team studies the novel welfare implications of this belief stabilization This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-09

Overall Project Summary/Abstract Prostate cancer has become the most frequently diagnosed cancer in men in the United States (US) and a major cause of cancer morbidity and mortality, with 33,000 American men (~90 every day) dying annually from the disease. Considerable progress over the last decade resulted in the approval of multiple new hormonal and cytotoxic therapies, each producing modest improvement in survival. Yet, despite a broad palette of therapeutic options and the emerging promise of immunotherapy, the cure of metastatic prostate cancer has remained elusive. However, over the past two decades, dedicated prostate cancer research, accomplished by Johns Hopkins Prostate Cancer Program investigators and other researchers, led to a remarkable accumulation of knowledge about the molecular mechanisms by which human prostate cancers arise and progress. These studies identified adaptive autoregulation of androgen receptor activity, mutations and alterations in DNA-repair pathways and an immunosuppressive microenvironment as fundamental characteristics of prostate cancer producing resistance to hormonal, DNA-targeted and immune based therapies and allowing for progression that eventually threatens life. To make significant advancement in the treatment of prostate cancer, the goal of this new Prostate SPORE application is to translate new insights about the role played by adaptive changes in the hormonal axis, DNA-repair and the immune system in the pathobiology of prostate cancer into new hypotheses tested in clinical trials. The transcendent overall objective of the Johns Hopkins Prostate Cancer SPORE is to reduce prostate cancer mortality via the focused pursuit of translational research in prostate cancer.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY: This is a submission for a National Institutes of Health R01 award called The BLAAST Project, which aims to conduct a randomized, double-blinded, placebo, non-inferiority trial of pediatric care enhanced by a novel automated digital stethoscope, compared to standard care, in Bangladesh (Aim 1) with an integrated implementation assessment (Aim 2) and economic evaluation (Aim 3) over three years among young, low-risk children with non-severe clinical pneumonia. Antibiotics are a mainstay of the treatment of acute lower respiratory infections in young children in low- and middle-income countries (LMICs) like Bangladesh even though most episodes are caused by self-limiting viruses. Innovative child friendly tools that improve the diagnosis of respiratory illnesses, safely reduce the unnecessary use of antibiotics, and are suitable for implementation in LMICs are urgently required to safely improve antibiotic stewardship and stem the rising rates of antibiotic resistance globally. In this project (Bangladesh Lung Auscultation Artificial Intelligence for Antibiotic Stewardship or BLAAST) we aim to utilize a novel FDA-approved digital stethoscope with automated lung sound analytics developed and validated over a period of ten years from evidence across seven LMICs. In Aim 1, we will determine whether treatment failure frequency among children in rural Bangladesh managed by clinical guidelines enhanced by a novel automated digital stethoscope is non-inferior to guidelines alone. We hypothesize treatment failure frequency among `enhanced IMCI' participants will be no worse than standard care by a +/-2% margin, safely reducing antibiotic use by 50-60%. In Aim 2 we will assess digital auscultation implementation and antibiotic use during pediatric respiratory care in rural Bangladesh to inform strategies of antibiotic stewardship. Lastly, in Aim 3 we will evaluate if a diagnostic strategy enhanced by an automated digital stethoscope is a sustainable alternative to standard care for children in rural Bangladesh. We hypothesize that care augmented by a digital stethoscope will have additional benefits via reduced antibiotic use that will outweigh digital auscultation costs resulting in cost-effectiveness compared to current practice. BLAAST affords a unique opportunity to evaluate the efficacy of clinical guidelines enhanced by an automated digital stethoscope on child pneumonia outcomes in Bangladesh, if digital auscultation may be instrumental in the wider antibiotic stewardship strategy, and whether a digital stethoscope diagnostic tool is cost-effective in the care of children with respiratory illnesses.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Loss of vestibular function causes visuospatial misperception, imbalance, and decreased visual acuity during head motion, leading to severe impairment of daily activities. Vestibular rehabilitation therapy is the standard of care for treating these associated symptoms, but it is not universally effective and there are no objective means for identifying mechanisms that contribute to the recovery when it is successful. Following loss of vestibular function, each patient may have a distinct predisposition toward relying on one or another sensory modality (e.g., vision or somatosensory inputs), or may adopt a different strategy to cope with the aberrant vestibular information (e.g., blink during head rotation). These intricate responses can result in different patterns of sensorimotor reorganization during recovery. Another major constraint rerated to vestibular recovery is the lack of objective assessments of otolith and semicircular canal function, as the current outcome measures instead rely on the clinician judgment. Such lack of quantitative measures of the vestibulo-ocular reflex (VOR) and other sensory substitutions preclude the ability to predict functional outcomes and identify those patients who could benefit most from rehabilitation. To address this issue, the objective of this project is to examine whether novel video- oculography (VOG) measures of the VOR can be used as valid markers of functional outcome following vestibular loss. To this end, we will use the video head impulse test (vHIT) to measure semicircular canal function. For assessment of the otolith function, we have developed a VOG method based on ocular counter-roll (vOCR), during which the torsional VOR is quantified with lateral head tilt. Our preliminary results show recovery in vOCR with vestibular compensation over time, whereas the VOR gain as measured by vHIT remains abnormal in all stages of recovery following vestibular loss. Some patients however generate compensatory saccades that conceal their VOR deficit, suggesting a saccade strategy that may be related to the adequacy of vestibular compensation. In addition, we have found that the difference in vOCR during en bloc head-and-body tilt versus head-only tilt can be used as a measure of sensory substitution for vestibular loss during recovery. Based on these findings, our central hypothesis is that vOCR with whole- body/head-only tilt and compensatory saccades with vHIT can be used as novel markers to (i) measure recovery and (ii) predict functional outcomes following vestibular loss. We expect that the findings in this project will also provide the basis for a future grant that investigates customized vestibular rehabilitation using discrete and easy- to-apply VOG measurements in individual patients rather than applying a fixed treatment protocol in all patients.

NSF Awards · FY 2024 · 2024-09

This project aims to challenge established narratives about women's political behavior after suffrage by investigating the roles of electoral institutions and political geography in shaping gender gaps in voter turnout and preferences. The theoretical contribution lies in developing a new framework that explains how electoral systems and political geography drive variations in women's political participation across different regions and geographic space. Specifically, it posits that proportional representation and compulsory voting systems both diminish gender gaps in turnout, but that preference gaps at the national level depend on how local political geography combine with the demography of turnout. Empirically, the project tests these propositions in cross-national and within-country investigations, focusing on places that enfranchised women from 1906-1945 and under-studied areas. These cases provide unique institutional variation vis-à-vis more highly studied cases. By integrating new political domains, the study can better test the theory that electoral competition and political geography significantly affect gender gaps after suffrage. The methods involve collecting and digitizing historical electoral returns and census data, cross-nationally and then with a sub-national focus on polling-station-level data and state-level data. Advanced AI-assisted transcription techniques will be employed to process handwritten records. This approach will enable a comprehensive analysis of the gender turnout gap and preference gap across different electoral systems. By leveraging these unique datasets, the project will provide new insights into the effects of electoral institutions on women's political behavior, contributing to a broader understanding of political participation. The findings will have significant implications for political development theories and will support the education and training of underrepresented students in quantitative research methods. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2024 · 2024-09

7. PROJECT SUMMARY / ABSTRACT Given the complex socio-structural barriers that PWID face, models of care need to shift from disease-centric models to status-neutral person-centric approaches that address non-HIV issues in addition to HIV services. Yet, few such models exist to date and of those that do exist, there has been little to no evaluation of their impact – including indirect effects on other risk groups and/or geographies. India is home to ~800,000 PWID, with HIV prevalence >20% in many cities. HIV incidence among PWID in New Delhi is 21.3 per 100 PY and less than 10 percent of PWID living with HIV are virologically suppressed. Additionally, a significant proportion of PWID in New Delhi report same-sex or opposite-sex partnerships and the majority report migrating to Delhi for work. Understanding these connections could help identify direct and indirect impacts this intense epidemic (and mitigation efforts) have on PWID in New Delhi and other populations and/or geographies or vice-versa. A status-neutral, person-centric clinic (the Blue Shed as referred to by the community) is being established at the venue that appears to be driving HIV transmission in New Delhi (opening March 2023). Our team is uniquely situated to evaluate the direct impact of this spatially-targeted person-centric intervention (Blue Shed) in a setting with one of the highest HIV incidence rates globally and indirect impacts across PWID networks and other groups. Our Specific Aims are to: Aim 1: Evaluate the impact of a spatially targeted status-neutral person-centric intervention on HIV incidence, viral suppression, and mortality among PWID in New Delhi, India; Aim 1a: Investigate the diffusion of a status-neutral person-centric intervention over networks and spaces; Aim 2: Quantify the overlap of HIV epidemics between PWID in New Delhi and other populations in New Delhi, as well as PWID across selected Indian cities, to elucidate potential indirect impacts of the Blue Shed intervention; Aim 2a: Examine the overlap between drug use and sexual networks of PWID through sociometric and egocentric network-based behavioral data and phylogenetic analysis; Aim 2b: Assess HIV source-sink dynamics and the geographic extent to which HIV among PWID in New Delhi overflows to PWID in neighboring states of Punjab, Uttar Pradesh, Chhattisgarh, and Manipur; and Aim 3: Model the direct and indirect impacts of a status-neutral person-centric intervention on HIV transmission within and beyond New Delhi alone and with other novel strategies (e.g., LA ART, LA PrEP). We will achieve these aims by 1) continuing follow-up of our sociometric network cohort of ~2500 PWID in Delhi; 2) establishing biometric linkages to the Blue Shed; 3) collecting new GPS data on mobility; 4) recruiting a sample of sexual partners of PWID; 5) leveraging behavioral data and specimens from large serial cross-sectional surveys (from 2013, 2016, 2023) among MSM in New Delhi and PWID in 4 other cities; and 6) whole-genome sequencing on specimens. Evaluating the impact of this novel Blue Shed intervention in a setting with extremely high incidence and low engagement in care presents a rare and time-sensitive opportunity to inform policy.

NIH Research Projects · FY 2026 · 2024-09

Occipital strokes cause permanent damage to primary visual cortex (V1), the gateway for visual information processing in humans. Such patients lose conscious vision in the contralateral visual field, termed cortically- induced blindness (CB), although unconscious visual processing sometimes remains in the blind field, known as blindsight. Importantly, visual discrimination training with moving stimuli placed just inside the blind-field border can restore some conscious vision in CB patients. However, overall visual capacities in the blind field remain highly impaired, making daily activities like reading and driving difficult or impossible. A number of neuronal pathways linking the visual thalamus (dorsal lateral geniculate nucleus, LGN) with extrastriate cortex directly, or indirectly through residual portions of V1, have been proposed to underlie blindsight and training-induced vision recovery, respectively. However, no direct measures of changes in the neurons and circuits connecting LGN, perilesional V1, and extrastriate cortex have ever been made after V1 lesions, especially simultaneously, and such invasive measures are not possible in humans. Here, we aim to fill this substantial gap by characterizing neuronal and circuit adaptations post-V1 lesions in a novel animal model of CB (Aim 1). We will then uncover reconfigurations that occur in these neurons and circuits following training optimized to attain vision restoration (Aims 2-4). Our overarching goals are to provide a mechanistic explanation for both blindsight and training- induced vision recovery, and to provide a foundation for improving current vision restoration therapies throughout the blind field. We will develop a CB model in ferrets, highly visual carnivores with early visual parallel processing streams and motion-selective extrastriate cortical areas homologous to those in primates. Ferrets have a large binocular visual field, unlike rodents, and can be trained to perform complex visual discrimination tasks, like humans and primates. Yet larger cohorts of ferrets can be tested and trained across a battery of stimulus para- digms than is possible in primates. Ibotenic acid lesions of V1 will be made to create vision loss in the central ~50˚. Multi-electrode arrays will be inserted simultaneously into 3 critical nodes in the residual visual system: LGN, perilesional V1, and the motion-selective postero-medial lateral suprasylvian (PMLS) area to test how direct LGN-PMLS and indirect LGN-perilesional V1-PMLS circuits are modified post-lesion (Aim 1). Separate cohorts of V1-lesioned ferrets will then be trained on custom regimes (Aim 2) inspired by neuronal response properties measured in Aim 1. This will allow assessment of neurophysiological adaptations induced by optimal training paradigms (Aim 3). Finally, retrograde tracing and neurochemistry will be used to determine the contri- butions of distinct cell types and neuronal circuits to passive plasticity (Aim 1) versus training-induced vision recovery (Aim 4). Together, these results will provide the most comprehensive picture yet of the neuronal mech- anisms engaged by V1 lesions, and how these differ between blindsight and training-induced visual recovery. This creates a critical scientific platform for future optimization of vision restoration in human CB patients.

NIH Research Projects · FY 2025 · 2024-09

Pluripotent-derived cardiomyocytes (PSC-CMs) remain immature in phenotype and function, and the lack of maturity has now emerged as a major concern in their clinical application. However, it remains poorly understood why PSC-CMs fail to fully mature. To address this, we have generated a high-quality, high-resolution single cell transcriptome map of endogenous CMs undergoing maturation and identified a critical window when a majority of genes change their expression levels. A direct transcriptomic integration with isogenic PSC-CMs has revealed a group of perinatal genes abnormally expressed in PSC-CMs, causing them to stall prematurely. Through comprehensive computational approaches, we further discovered a conserved gene regulatory network of dysregulated transcription factors that underlie maturation failure. In light of these findings, this project aims to test the role of the gene network in overcoming the premature arrest of PSC-CMs. This knowledge will pave the way for a transcriptome-based strategy for PSC-CM maturation, which can be leveraged towards improving clinical viability of PSC-CMs.

NSF Awards · FY 2024 · 2024-09

This NAIRR-Pilot project introduces an innovative artificial intelligence (AI) integrated framework to dramatically enhance the efficiency and accessibility of exascale multiphysics simulations, addressing the critical challenge of enabling comprehensive parameter space exploration at unprecedented scales. While exascale simulations represent the pinnacle of supercomputing power, their significant computational demands have hindered comprehensive parameter testing, crucial for scientific discovery and engineering optimization. The approach integrates advanced AI techniques with traditional numerical methods, democratizing access to exascale-level insights without sacrificing accuracy. Key innovations include a novel spatial coupling mechanism between AI and numerical solvers, efficient communication techniques for distributed computing, and adaptive learning methods that quickly adjust to emerging behaviors at the exascale level. The coupling of pre-trained AI models with numerical solvers allows for rapid solution generation for large portions of the domain. The numerical solver is selectively deployed in critical sections where complex physical processes occur, ensuring high accuracy while significantly reducing computational costs. This NAIRR-Pilot project democratizes access to advanced AI research capabilities in computational science, enabling efficient parametric sweeps of exascale simulations. Serving as a crucial testbed for integrating AI resources with exascale scientific computing applications, it contributes to NAIRR's mission of broadening access to cutting-edge AI research tools to solve global challenges like climate change and future manufacturing. The project aligns with national priorities in maintaining leadership in high-performance computing and AI via educational initiatives to cultivate the next generation of diverse STEM talent through coding clubs for children and teens, inspiring future scientists, and fostering community engagement with open-source computational tools. The project develops a hybrid spatial coupling framework by integrating graph neural network-based neural operators with traditional numerical solvers. This integration maintains the accuracy of simulations while greatly improving computational speed, enabling efficient parametric sweeps of exascale multiphysics simulations. The approach includes probabilistic sampling-based message passing to optimize communication in distributed machine learning and hierarchical federated learning to enhance reduced-order model (ROM) predictions through efficient in situ learning and model adaptation in exascale environments. Additionally, one-shot learning techniques enable ROMs to adapt to new dynamics quickly using limited high-fidelity data. The project demonstrates this transformative approach by benchmarking against carbon capture processes and additive manufacturing problems as a proof of concept. The methodology significantly reduces computational expenses while maintaining high accuracy, potentially enabling comprehensive parametric studies of complex multiphysics problems at the exascale level. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-09

NSF FAIROS Research Coordination Networks (RCNs) work to build and enhance coordination of researchers and other stakeholders advancing Findable, Accessible, Interoperable, and Reusable (FAIR) data principles and Open Science (OS) practices. The initial cohort of 10 awards span a wide range of disciplines and have advanced FAIR-OS efforts as well as convened RCN-specific events. To broaden their impact and focus future directions, it is an appropriate time to take stock of RCN efforts and work together to both contextualize successes and clarify gaps as needed to plan sustained efforts in FAIR and Open Science across the US Science research landscape. This PI Meeting will support a community-driven and community-focused effort to help define the role that federal agencies can play in accelerating the pace of FAIROS. The workshop will bring together the research teams in their varied stages of maturity to encourage and support those in their early years while providing new ideas for more mature efforts facing persistent gaps. 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.