Grants

NSF

Nontechnical Description: This project will advance the understanding of nano-polaritons—waves that combine light and matter and travel within nanoscale materials. These waves can be used to control energy and information at extremely small scales, offering potential for faster optical computing, more efficient energy use, and advanced sensing technologies. The research team will explore how these waves behave when moving across materials of different shapes and sizes. These new setups for nano-polaritons could lead to more efficient ways to send and control information and energy at the nanoscale. The research will also support hands-on education and outreach for the general public on state-of-the-art optics and materials research. In addition, the project will integrate the research products into university coursework and involve K-12 participants in summer activities. Undergraduate students will receive comprehensive training in nanomaterial fabrication and optical simulations, helping prepare the next generation of researchers in optics, materials science, and engineering. Technical Description: This project will investigate cross-interface polariton nano-light in heterostructures formed by mixed-dimensional and reduced-symmetry materials. By breaking the traditional symmetric behaviors of polaritons, the research will enable the discovery of unconventional light-matter interactions and propagating nano-optical modes over quantum-confined nanostructures. The principal investigator will explore different dimension configurations to vary the polariton propagation characteristics. The project will also utilize materials with low crystal symmetry and extreme optical anisotropy to enable non-reciprocal, directional, and non-symmetric polariton nano-light. Scattering-type scanning near-field optical microscopy will be used to provide direct visualization of polariton nano-light behaviors with nanometer resolution. At the same time, finite element method simulations will be conducted to offer theoretical insights into field distributions and dispersion relations of the polaritons. Together, these methods will elucidate the mechanisms of polariton energy transfer and photonic density of states enhancement at the nanoscale interfaces. These polaritonic heterostructures are expected to yield novel optical phenomena that cannot be achieved in conventional systems or material combinations. The research outcomes will contribute to the fundamental understanding of nanoscale optical energy transport and hold promises for practical applications such as fast photonic circuits, efficient energy transport, precise biomedical treatment, effective thermal management, and quantum information and communication. This research may also expand current knowledge in physics and optics by revealing novel mechanisms of nano-light propagation and energy transfer at intriguing nano-interfaces. 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.

NIDA - National Institute on Drug Abuse

Cocaine use disorder (CUD) is a highly prevalent in people living with HIV (PWH), and co-occurring HIV and CUD result in poorer clinical outcomes and more severe neurocognitive sequelae. Despite exacerbated risk for behavioral and cognitive deficits in PWH who use cocaine, there is limited understanding and an absence of targeted therapeutic strategies addressing the effects of CUD and HIV on the brain. Better definition of the interaction between cocaine use and HIV infection in the CNS is essential to address this knowledge gap. HIV and CUD both increase neuroinflammation via activation of inflammasomes, multiprotein complexes that regulate inflammation through production of the cytokines IL-1β and IL-18. NLRP3, the most widely studied inflammasome, is highly expressed in microglia, as well as other CNS myeloid cells. Cocaine exposure and HIV infection can both activate NLRP3. While processes regulating inflammasome activity are well-defined, the mechanisms by which HIV and cocaine affect them are not. Cocaine increases dopamine in the mesolimbic region. Increased dopamine appears to mediate the effects of cocaine effects on inflammasomes, as cocaine use upregulates NLRP3 expression and IL-1β in the mesolimbic region in vivo (when it increases dopamine levels), but not in microglia in vitro. HIV infection also disrupts dopamine reuptake and metabolism and increases inflammation in mesolimbic structures. This suggests that cocaine use and HIV infection interact via dopaminergic dysregulation, potentiating regional neuroinflammation and disrupting behaviors and cognitive processes defined by mesolimbic circuits. The mechanistic link between dopamine and inflammasomes is not clear, but mitochondrial dysregulation has been shown to regulate inflammasome activity in myeloid cells. Our preliminary data show that dopamine increases NLRP3 activity in human iPSC-derived microglia in vitro, and that in human macrophages, dopamine specifically enhances caspase expression and Gasdermin cleavage. In these human macrophages, dopamine also disrupts mitochondrial fission, and blocking the effects of dopamine on mitochondrial fission inhibits the dopamine-enhanced in inflammasome activity. We also show that HIV and cocaine interact to drive inflammation and disrupt reward-seeking behavior in vivo in EcoHIV-infected mice self- administering cocaine, which correlates with other studies showing that cocaine mediated inflammation impairs drug seeking behavior and cognitive function. Thus, we hypothesize that cocaine-mediated increases in dopamine potentiate inflammasome activation in microglia in the HIV-infected CNS by dysregulating mitochondria and enhancing neuroinflammation, which contributes to cognitive deficits and aberrant reward seeking. Our proposal addresses this hypothesis in in vitro, ex vivo and in vivo models at the single cell (Aim 1), circuit and behavioral (Aim 2) levels. This will generate of data from complementary human and rodent systems to overcome the limitations inherent in any single neuroHIV model and generate interconnected data sets correlating functional, and behavioral changes in response to HIV and cocaine use.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary Damage to the nervous system results in the death of many neurons, leading to adverse outcomes such as locomotor and cognitive defects. Neural injuries may induce neuroplasticity responses in surviving neurons, where they extend their axons and dendrites and form new connections (undergo rewiring) to cope with the loss of their neighboring neurons. Neural circuits are composed of different neuronal types, each with unique intrinsic properties such as neural firing patterns, neurotransmitter identity, and synapses of different types and sizes. Whether different neuron and synapse types are equally capable of undergoing structural plasticity remains unclear. Furthermore, the role of non-neuronal cells (such as glia and muscles), intercellular signaling pathways, and cross-talk between neurons, glia, and muscles during the plasticity response are still under investigation. Addressing these knowledge gaps will help optimize therapeutic strategies, thereby maximizing the chance of the restoration of circuit function after neural injury. The objective of this proposal is to address these problems using the motor circuits underlying locomotion in Drosophila larvae. Two types of motor neurons (MNs) form neuromuscular junctions (NMJs) with larval body wall muscles: tonic-firing MNs with large NMJs and phasic firing MNs with small NMJs. These MNs receive input from excitatory and inhibitory premotor neurons (PMNs). In addition, different subtypes of glial cells in Drosophila are functionally and morphologically comparable to those found in vertebrates. The rich genetic toolkits in larvae provide an unprecedented opportunity to determine how PMN-MN-muscle circuits rewire in response to the death (or inactivation) of PMN and MN subsets and determine the role of glial and denervated muscles in mediating proper circuit rewiring. For the first time, strong preliminary data provided in this proposal demonstrate that in response to the death of MN subsets, the motor axon of a single surviving MN extensively sprouts and forms new NMJs on denervated muscles, recovering their contractility. Expanding on this experimental setup, Aim-1 will test the hypothesis that tonic-firing MNs and excitatory PMNs are more potent than phasic MNs and inhibitory PMNs to rewire and form new synapses upon loss of their neighboring neurons. Aim-2 will determine whether debris clearance and path formation by glial cells are prerequisites for sprouting and rewiring of PMN-MN-muscle circuits that survive post-injury. In parallel, Aim-2 will experimentally test a model based on which glial cells and denervated muscles release neurotrophic factors that instruct surviving MNs to form new synapses (i.e., new PMN-MN and MN-muscle connections) in proper locations. It is expected that this research will provide a deeper understanding of motor circuit recovery mechanisms mediated by synaptic plasticity that are conserved in mammals, and generate hypotheses to be tested in vertebrate locomotion.

NSF

With support from the Chemical Synthesis Program in the Division of Chemistry, Professor Gojko Lalic at the University of Washington is studying the development of new reactions for the synthesis of organic molecules using organoboron compounds and transition metal catalysis. The project is advancing more efficient transformations of common starting materials into more valuable targets, complementing existing methods. These reactions are providing a new approach to forming carbon-carbon bonds, critical for constructing large organic molecules. Beyond practical applications in organic synthesis, the fundamental properties and reactivity of organoboron compounds are being investigated and expanded in these studies. An essential part of the project is its outreach initiative, which fosters connections with the local community. Dr. Lalic's team engages elementary and high school students through activities that inspire interest in science, technology, engineering, and mathematics (STEM) careers. Organoboron compounds are valuable synthetic building blocks due to their availability, stability, and versatile reactivity. Continued advances in the synthetic applications of these compounds is critically important to support the pharmaceutical industry, medicinal chemistry, the synthesis of agrochemicals, and material science. Prof. Lalic and his research team are creating more effective tools for synthesizing complex organic molecules by exploring two new classes of chemical reactions. The first is a new type of cross-coupling reaction using two nucleophilic coupling partners that leverages the ambiphilic nature of organoboron compounds and the ability of transition metal complexes to modulate their reactivity. The second focuses on innovative strategies for homologating organoboron compounds via formal insertion of C2 fragments into carbon-boron bonds. Notably, this C2 fragment insertion involves an unusuallly facile activation of carbon-carbon bonds. Integral to this work are outreach activities, which are designed in collaboration with the local community, to promote science education and engagement. 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.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary Hemagglutinin (HA) antigenic changes of influenza (flu) viruses and low immunogenicity of conventional flu vaccines result in suboptimal efficacy, ranging between 10% and 60%, and much lower efficacy or no protection against pandemics. It is a high priority to design new universal flu vaccines, develop a novel vaccination strategy, and better understand the innate and adaptive immune mechanisms for vaccine- mediated effective protection. The mRNA vaccine platform would provide many advantages over conventional vaccines. In this project, we designed new mRNA vaccine constructs encoding neuraminidase (NA) conjugated to a highly conserved M2e repeat, which is based on our prior studies reporting that immunity to both NA and M2e could provide broad cross-protection against different subtypes and lineages of flu A and flu B viruses. However, non-neutralizing immunity to conserved domains would have limited efficacy despite broader protection. Lipid nanoparticles (LNP) encapsulating mRNA vaccines are known to be inflammatory. High doses of mRNA LNP vaccines would cause undesirable side effects. We hypothesize that mRNA LNP vaccine targeting conserved domains and inducing cross-protective immunity will enhance the broad cross- protection of co-administered conventional flu split vaccines at low doses of both vaccines. This hypothesis is supported by our new preliminary data demonstrating that a combination of flu A 5xM2e mRNA or B NA mRNA LNP and inactivated split virus vaccines significantly enhanced the efficacy of cross-protection against flu A and flu B viruses. Flu A (not flu B) has pandemic threats, more diverse natural hosts, and antigenic diversity, and is highly pathogenic, rendering flu A viruses more challenging to control than flu B. In Specific Aim 1, we will further test the hypothesis that the combination of new cross-protective mRNA LNP and inactivated flu A virus split vaccines will provide higher efficacy of homologous and heterologous against flu A viruses. In addition, we do not fully understand the innate and adaptive immune mechanisms of how adding an mRNA LNP vaccine to conventional inactivated split virus vaccination will enhance homologous and heterologous protection. In Specific Aim 2, we will determine whether a combination of an mRNA LNP vaccine and conventional inactivated flu split vaccines will activate a unique set of innate immune responses leading to enhanced adaptive immunity. We expect that the outcomes of this project will provide insight into innate and adaptive immune correlates with enhanced homo- and cross-protection by a combination of cross-protective mRNA and conventional vaccines, in addition to developing a new vaccination strategy inducing enhanced protection against seasonal and pandemic potential variants.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary/Abstract Brain bleeding in the parenchyma, also known as intracerebral hemorrhage (ICH), represents 10 to 30 percent of strokes in distinct countries around the world. Despite its lower incidence than ischemic stroke, ICH carries higher rates of mortality and morbidity. Worse outcomes in humans with ICH have been correlated with damage to axons in areas of the brain like the thalamus or the striatum where bleeding from small, penetrating arteries (often affected by longstanding hypertension) tends to occur. Red blood cells accumulate in ICH and lyse and release toxins. These include hemoglobin (Hgb) and its breakdown product hemin . Additional understanding of how Hgb/hemin leads axons to degenerate in ICH is a strategy to fully assess and overcome disability from this condition. Excitingly, a molecular path for programmed axonal destruction has been defined involving the protein, sterile alpha and Toll/Interleukin receptor-1 (TIR) motif containing 1 (SARM1). SARM1's degenerative activities in the axon emerge from its NADase (NAD+ degrading) activity in the TIR domain. This domain's importance is highlighted by its conservation from plants to humans. In preliminary studies, we found that germline deletion of full length SARM1 prevents axonal damage in the striatum following ICH. Since previous studies from our lab have shown that hemin induces ferroptosis, an iron-dependent, caspase-independent form of programmed necrosis, following experimental ICH, we are seeking to understand the cross talk between ferroptosis and SARM1-mediated axonal destruction (sarmoptosis). Of note, we found that cortical neurons cultured from the SARM1 knockout mice are partially resistant to ferroptotic stimuli (hemin and erastin). Moreover, agents such as P7C3 that augment the cell's ability to make NAD+ protect against ferroptosis; conversely, FK866, which impedes the same NAD+ synthesizing pathway makes ferroptosis worse. From these preliminary studies we propose three aims designed to understand the interplay between ferroptosis and sarmoptosis in ICH. In the first aim, we will leverage mice that possess a germline, homozygous, single amino acid mutation (E642A) in the NADase domain of SARM1. Like the SARM1-/- mice, the neurons of these mice are resistant to axotomy in vitro and in vivo. They will be used to probe whether the NADase activity is critical for ferroptosis in vitro and ICH in vivo. In the second aim, we will address the hypothesis that hemin-induces axonal degeneration via local ferroptotic pathways that trigger SARM1 activation. We will use sensory neurons cultured in Campenot Chambers to isolate cell bodies from axons and query their possibly distinct responses to lethal concentrations of hemin. We will also probe the role of ferroptosis and sarmoptosis in the destruction of corticospinal tract axons in vivo. In the last aim, we will seek to understand whether interventions that target ferroptosis by acting in the nucleus (cell body) can be combined with SARM1 deletion (that acts primarily in axons) in mice to reduce damage and improve behavioral recovery over each agent tested alone. At the culmination of these studies, new mechanistic information will emerge regarding axonal and cell body loss following ICH with clear therapeutic implications.

U.S. National Science Foundation

Crosscutting Activities in Materials Research

Crossett Economic Development Foundation

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

NIDCD - National Institute on Deafness and Other Communication Disorders

PROJECT SUMMARY Sensory loss leads to widespread adaptation across the brain areas to enhance processing of the remaining senses as exemplified by enhanced auditory functions in blind individuals. Such crossmodal compensatory plasticity is not restricted to congenitally blind individuals but is also observed after late-onset vision loss. We previously found that visual deprivation initiated in adult mice leads to widespread synaptic and circuit-level plasticity in the auditory pathway: potentiation of feedforward inputs carrying auditory information in the primary auditory cortex (A1), including recovery of thalamocortical synaptic plasticity, functional refinement of local circuitry in A1, and disinhibition of the primary auditory thalamus. These changes correlated with a reduction in the sound detection threshold and sharper tuning of A1 layer 4 (L4) neurons as well as refinement of sound representation in A1 L2/3. Here, we propose to test the hypothesis that such widespread plasticity of the auditory system following visual deprivation is functionally coordinated by the plasticity of the corticothalamic (CT) circuit. There are largely three distinct CT circuits: (1) Lemniscal CT pathway mediated by A1 L6 neurotensin receptor 1 (Ntsr1)-positive neurons, which provide cortical feedback to the primary auditory thalamus (MGBv) and the inhibitory thalamic reticular (TRN) nucleus, (2) non-lemniscal CT pathway mediated by A1 L6b neurons (Cplx3 and Drb1a-positive), which project to higher order non-lemniscal thalamic nuclei, and (3) cortico-thalamo-cortical (CTC) pathway mediated by A1 L5 neurons (Rbp4-positive), which project to higher-order auditory cortical areas via the higher-order auditory thalamic nuclei. We aim to investigate how early- and late-onset visual deprivation alters the function of these CT circuits in adult mice (Aim 1), whether it affects CT circuit regulation of feedforward auditory pathways (Aim 2), and determine how it alters the sound encoding of CT neurons (Aim 3). We will utilize optogenetics to assess the plasticity of functional circuits, multi- photon Ca2+ imaging accompanied by auditory behavioral tasks to measure neural activity changes, and pharmacogenetics for testing neural circuit elements on in vivo function and behavior. Results from our work will provide mechanistic information on how the CT circuit mediates crossmodal compensatory plasticity in early- and late-onset blind models, which would benefit the development of potential therapeutics for improving sensory function.

Crossroads College Foundation

Crossroads College Foundation is an active grantmaking foundation based in Rochester, MN. Focus: education. Contact the foundation directly for current funding opportunities.

Town of Centreville

Crossroads Community Facility

Town of Centreville

Crossroads Community Facility

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Research supports a role for reduced cholesterol efflux and lipid droplet (LD) accumulation in mitochondrial dysfunction (MD) and podocyte injury in the pathogenesis of glomerular diseases of metabolic and non-metabolic origin, including Alport Syndrome (AS). Less is known about the contribution of triglyceride (TG) accumulation in LDs to MD and podocyte injury. LDs regulate the storage and homeostasis of intracellular TGs and regulate the availability of free fatty acids (FFAs), which can be oxidized in mitochondria and used as an energy source. Proper contact of LDs with mitochondria is mediated by LD-associated proteins, such as perilipin 5 (PLIN5), and is instrumental for FA synthesis and breakdown. PLIN5 is a protein that regulates TG metabolic pathways and cellular energy homeostasis through its role in the lipolysis of TGs stored in LDs, mediates LD-mitochondrial contact formation, and serves as a substrate for chaperone-mediated autophagy (CMA). However, little is known about the function of PLIN5 in podocytes. In preliminary data, we demonstrate decreased PLIN5 expression in glomeruli of patients with AS, in kidneys of Col4a3 KO (AS mice) and AS podocytes, and in a zebrafish model of AS when compared to controls. In AS podocytes, PLIN5 deficiency is associated with increased lipolysis, FFA accumulation, and reduced LD- mitochondrial contact formation and mitochondrial membrane potential, which was restored by PLIN5 overexpression. AS podocytes have an increased autophagosome number compared to WT, often in proximity of mitochondria, suggesting increased mitophagy. PLIN5 expression is restored by Ezetimibe (EZ), a compound that we found to partially protect AS mice from the development of proteinuria. Our results suggest an important role for PLIN5 deficiency in lipotoxicity-induced MD and podocyte injury and renal disease progression in AS. The overall goal of this proposal is to investigate a novel mechanism linking PLIN5 deficiency to lipotoxicity- mediated MD, CMA and podocyte injury in AS. We hypothesize that PLIN5 deficiency in AS causes TG-rich LD accumulation due to impaired CMA, FFA accumulation due to increased TG lipolysis and impaired LD-mitochondrial contact formation, resulting in lipotoxicity-induced mitochondrial dysfunction. We propose a combined in vitro and in vivo approach to investigate the mechanism by which PLIN5 deficiency causes lipotoxicity-induced MD and podocyte injury (aim 1), and in renal failure (aim 2) in AS. If successful, this innovative study will link PLIN5 deficiency to a novel pathway of lipotoxicity-induced MD and podocyte injury and may lead to the identification of new drug targets for the treatment of patients with proteinuric kidney diseases associated with altered GBM, such as AS.

NIEHS - National Institute of Environmental Health Sciences

Project Summary Environmental and endogenous genotoxic stressors can induce DNA and RNA damage and misdeposition of the epitranscriptomic mark, N6-methyladenosine (m6A), leading to genome instability, gene dysregulation, and cancer and neurodegeneration. However, it remains unknown how DNA and RNA damage can synergize to modulate genome and epitranscriptome stability. In this project, we aim to understand the mechanisms underlying the crosstalk of RNA damage and m6A with DNA damage and repair. Our hypothesis is that environmentally-induced RNA damage, m6A, and DNA base damage and repair can interplay on R-loops to modulate RNA and DNA integrity. To test the hypothesis, we will pursue three Specific Aims. Aim 1 is to determine if environmentally-induced RNA damage can modulate RNA-guided DNA base damage repair and its fidelity on R-loops. First, we will determine if the environmental genotoxicant KBrO3 and occupational exposure level of Mn2+ can induce RNA and DNA base damage on R-loops to disrupt the expression of R-loop hotspot genes, MALAT1 and unfolded protein response regulator X-box binding protein 1 (XBP1) genes in human kidney cancer and iPSC-differentiated neural cells. Second, we will determine if RNA base damage can promote KBrO3- and Mn2+-induced DNA base damage by reducing the efficiency and fidelity of RNA-guided BER using circular RNA-mediated RNA damage systems, the artificial intelligence tool AlphaFold3, molecular dynamics simulation (MD), and steady-state enzyme kinetics. Aim 2 is to determine if m6A can modulate environmentally-induced DNA base damage repair by regulating RNA-guided DNA synthesis on R-loops. First, we will determine if KBrO3 and Mn2+ can cause the unique m6A deposition on R-loops, leading to dysregulation of the MALAT1 and XBP1 genes in kidney cancer and neural cells. Second, we will determine if m6A can disrupt DNA base damage repair induced by KBrO3 and Mn2+ on the R-loops of the MALAT1 and XBP1 genes by altering BER efficiency and fidelity using circRNA-mediated gene-targeted m6A deposition systems, AlphaFold3, MD, and enzyme kinetics. Aim 3 is to determine if environmentally-induced DNA base damage and repair can modulate m6A deposition on R-loops to disrupt RNA transcriptomic integrity. First, we will determine if KBrO3- and Mn2+-induced DNA base damage can alter m6A deposition on R-loops of the MALAT1 and XBP1 genes by disrupting the recruitment of m6A writers METTL3/METTL14 and eraser FTO and their substrate interaction on R-loops, suppressing R-loop resolution and expression of the genes in cancer and neural cells. Second, we will determine if DNA base damage can synergize with Mn2+ to cause m6A misdeposition on R-loops of the MALAT1 and XBP1 genes. Our study will create a new paradigm to reveal the crosstalk between environmentally-induced oxidative RNA damage and m6A deposition and DNA base damage and repair on R-loops in modulating genomic and transcriptomic integrity. Our results will facilitate the discovery of novel targets for RNA-based gene-targeted therapy and biomarkers for the prevention of environmentally-induced cancer and neurodegenerative diseases.

Regional Council Capital Fund - RC4

Crouse Hospital Emergency Department Capital

Crown Family Foundation

Crown Family Foundation is an active grantmaking foundation based in Chicago, IL. Focus: philanthropy. Contact the foundation directly for current funding opportunities.

JOBS NOW 100

Crown Holdings Capital

Crusaders Health Foundation

Crusaders Health Foundation is an active grantmaking foundation based in Rockford, IL. Focus: philanthropy. Contact the foundation directly for current funding opportunities.

NIAID - National Institute of Allergy and Infectious Diseases

Varicella-zoster virus (VZV) is a human alphaherpesvirus of medical importance that can have severe outcomes in immunocompromised children and adults, causes debilitating diseases such as post herpetic neuralgia, and is linked to stroke. Like other herpesviruses, VZV relies on multiple glycoproteins for cell entry, tropism, and immune evasion, but their structural mechanisms remain poorly defined. Among these, gB and gH-gL constitute the core fusion machinery required for cell entry, while gE/gI plays a key role in viral replication and immune recognition. Despite their essential functions, high-resolution structures of complete glycoprotein complexes remain unresolved, limiting our understanding of herpesvirus membrane fusion and immune targeting. This study will leverage CyclApol-based membrane extraction and single-particle cryo-electron microscopy (cryo-EM) to define previously unobserved near-atomic resolution structures of VZV glycoprotein complexes in their native membranes. We will determine the structures of gB/gH-gL, providing critical insights into herpesvirus fusion, and gE/gI, defining its role in viral spread and antibody recognition. Guided by our strong preliminary data we propose to pursue two aims: (1) To determine the gB/gH-gL fusion complex structure and define its relationship to function; (2) To determine the structure of the gE/gI complex independently or interacting with antibodies. Preliminary data confirm the successful purification of both gB/gH-gL and gE/gI complexes from VZV-infected cells, demonstrating the feasibility of their structural determination. Our approach overcomes the limitations of computational modeling based on AlphaFold and similar platforms, circumventing their inability to accurately predict dynamic protein-protein interactions within membrane-associated complexes. By capturing glycoproteins in their native lipid environment, we will provide a structural framework for understanding viral entry and immune recognition at near-atomic resolution. These studies will set the stage for new approaches in herpesvirus structural biology, enabling the mechanistic understanding of membrane fusion, viral spread, and immune recognition at near-atomic scales while laying the groundwork for rational vaccine design and targeted antiviral therapies.

NINDS - National Institute of Neurological Disorders and Stroke

Title: Cryptococcal Nanotherapy: Engineering a Novel Fungus-Based Platform for Improved Drug Delivery to the Central Nervous System PROJECT SUMMARY/ABSTRACT Neurodegenerative diseases affect more than 1.2 billion people worldwide and this figure is steadily increasing. The exact causes of neurodegenerative diseases are still not entirely understood and the FDA-approved options for such diseases, especially amyotrophic lateral sclerosis (ALS), have very minimal effects on disease progression. This limited efficacy can also be attributed to the physiological barriers of the central nervous system (CNS), the physicochemical properties of the drugs, and the lack of understanding of how the drugs impact ALS. Riluzole and Edaravone, two FDA-approved drugs for ALS, possess the ideal properties for penetrating the CNS. However, their mechanisms of action in ALS remain unclear, they are likely to be absorbed by off-target tissues and can be ejected from the CNS barriers after ALS onset. Resveratrol has been cited as a potential alternative to existing therapeutics for ALS after demonstrating neuroprotective properties in preclinical animal models of ALS and is currently being investigated in clinical trials. Resveratrol is a polyphenolic molecule that scavenges reactive oxygen species and reduces oxidative stress in neuronal mitochondria, two hallmarks of ALS. Like Riluzole and Edaravone, resveratrol experiences off-target tissue absorption. The drug delivery field has sought to address this challenge by encapsulating resveratrol with nanomaterials. Despite some success, the nanoscale formulations of resveratrol are still limited by physiological barriers and the body's clearance mechanisms. Therefore, there is a critical need for a drug delivery platform that can withstand the body's clearance mechanisms and bypass the physiological barriers of the central nervous system to enhance ALS treatment. This work proposes using the neurotropic fungus Cryptococcus neoformans (Cn) to facilitate more efficient delivery of resveratrol into the central nervous system to treat ALS. Cn is well-equipped to traverse the physiological barriers of the central nervous system by “professionally” executing three separate mechanisms to penetrate the tissue: (1) paracellular transport (2) transcellular transport (3) immune cell hitchhiking and subsequent vomocytosis. Vomocytosis is a process by which Cn liberates itself from the intracellular environment of phagocytes to promote its survival. Given these unique characteristics, Cn is an ideal candidate for engineering the desired drug delivery platform as it can bypass physiological barriers to penetrate the CNS and escape premature degradation by the immune system. The overall hypothesis is that by tethering nanoparticle- loaded resveratrol onto the surface of Cn we can improve resveratrol delivery to the CNS and modulate ALS disease progression more effectively. To address this hypothesis, the first aim will optimize the synthesis of fungal drug carriers (FDCs) and assess their functionality in vitro. The second aim will evaluate the biodistribution of FDCs, quantify the bioavailability of resveratrol in the CNS, and investigate the therapeutic efficacy of the FDCs in a preclinical ALS model. A more efficient drug delivery platform that more effectively traffics resveratrol to the CNS will not only enhance the ALS treatment but also enhance treatment for other neurodegenerative diseases.

NSF

PART 1: NON-TECHNICAL SUMMARY This project, supported by the Solid State and Materials Chemistry Program in NSF’s Division of Materials Research, is focused on creating new materials by stacking ultra-thin layers of different elements. When these layers are combined in just the right way, they can show surprising behaviors, such as conducting electricity in unusual ways or reacting to magnets in ways we do not see in everyday materials. By carefully growing these materials into high-quality crystals, the principal investigator and her research group at Baylor University explore how the arrangement of layers leads to these unexpected effects. The goal is to better understand how the structure of a material impacts what it can do. Using advanced tools and techniques, this research could lead to the discovery of new materials that power future technologies like quantum computers and next-generation electronics. In addition, this project provides opportunities for student training in multi-disciplinary research and enables science-themed outreach in partnership with the Texas School for the Blind and Visually Impaired. PART 2: TECHNICAL SUMMARY With this project, supported by the Solid State and Materials Chemistry Program in NSF’s Division of Materials Research, researchers at Baylor University investigate the growth and characterization of high-quality single crystals of rare earth layered antimonides and tellurides, materials that offer fertile ground for discovering emergent physical phenomena. Comprising intergrown, structurally distinct subunits, these compounds provide a platform for probing correlated electron behavior, topological phases, and exotic magnetic orders. The significance of this work lies in its potential to uncover higher-order emergent properties, complex behaviors that arise from the interplay of multiple quantum phenomena and cannot be predicted from the properties of individual components alone. By leveraging recently discovered structure types within a tunable system, this study advances critical insights into how structural intergrowth drives the formation of novel quantum states. The research integrates thermal analysis, in situ experimentation, bulk crystal growth, and systematic investigations of electronic and magnetic properties in single crystals. Through the strategic selection of structural systems and the application of advanced methodologies, this work establishes a foundational framework for the development of heterostructure-inspired two-dimensional materials. The anticipated outcomes will significantly advance the understanding of emergent quantum phenomena and contribute to the design of next-generation functional materials with potential applications in quantum information science, spintronics, and other transformative technologies. 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.

Middletown

Crystal Lake Aerator

NSF

NON-TECHNICAL SUMMARY: Two-thirds of polymers are semicrystalline, and these are among the most widely and extensively used materials in our lives. Controlling the crystalline and amorphous structures that make up all semicrystalline polymers remains a fundamental issue for developing and optimizing their properties and applications. It is therefore important to understand the crystalline and amorphous structures of semicrystalline polymers. Most previous work focused on analysis of the crystalline structures. In this project, the PI aims at understanding the amorphous structure and the crystalline-amorphous interface of semicrystalline polymers. Using advanced spectroscopic techniques to understand interfacial and amorphous structures together with their crystalline counterparts, and studying dynamical processes, the project is focused on elucidating the crystallization and molecular re-organization pathways of semicrystalline polymers. A successful project will contribute to controlling the structures and properties of semicrystalline polymers and developing novel energy-efficient processing approaches. TECHNICAL SUMMARY The crystallization pathways of semicrystalline polymers have been debated for many decades, partly as a result of lack of understanding of the amorphous structure in the initial state as well as during the crystallization process. In this project, the PI and his team aim at elucidating the amorphous structure of semicrystalline polymers, making use of structural information obtainable through advanced techniques. 13CH3-labeled poly(L-lactic acid) (PLLA) and 13CH-labeled poly(D-lactic acid) (PDLA) racemate, which form stereocomplex crystals, are chosen as a model system. The PI will analyze intermolecular distances between PLLA and PDLA and fractions of closely paired racemate in both amorphous and crystalline regions by applying state-of-the-art solid-state NMR spectroscopy. Direct comparisons of the amorphous and crystalline structures will be used to elucidate the crystallization pathway of PLA racemate. In a second thrust, molecular-level information about the reorganization process upon heating of solution- and melt-grown PLLA crystals will be obtained by quantitative analysis for chain-folded structures at the crystal-amorphous interface in addition to crystalline chain dynamics. In both topics, molecular weight effects will be investigated. Ultimately, fundamental understanding of amorphous and interfacial structures will contribute to revealing the crystallization and re-organization pathways of semicrystalline polymers. 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

Oregon State University-Cascades, in collaboration with the University of Oregon and Portland State University, will address the challenge of building, expanding and sustaining high-quality computer science (CS) programs in K-12 schools throughout Oregon. The project team will investigate how teacher preparation, retention, and school-level administrative support create lasting CS educational opportunities for all students and investigate how this comprehensive approach creates lasting pathways for expanding and sustaining CS education across Oregon. The project outcomes will benefit society through having a more computationally literate pipeline of students for college, careers, creative endeavors, and civic participation. The CS for Oregon CSforAll High School Strand Research-Practice Partnership brings together expertise in Computer Science Research, Education Research, and High School teaching practice and works closely with key personnel from the Oregon Department of Education (ODE) such as the Oregon team participating in the NSF-sponsored Expanding Computing Education Pathways (ECEP) Alliance. The project staff will prepare existing teachers with any credential to teach Exploring Computer Science, an evidence-based course shown to engage all students. Alongside teacher preparation, the project researchers will support and study how experienced CS teachers deepen their practice through action research while building agency as educational leaders to expand and sustain CS. This bottom-up approach is complemented with top-down support for teacher leaders by preparing administrators to move from passive engagement to knowledgeable and active champions of rigorous and evidence-based CS. This project will contribute significant new knowledge about the educator workforce needed to establish and maintain evidence-based, rigorous, foundational CS education, with particular attention to how school systems can be developed and networked to support program sustainability, especially in rural and high-poverty communities. 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.