This page lists the previous ten years of Research Seed Award winners. For information about earlier funded projects, please email [email protected].
High-Intensity Water-Assisted Laser Desorption-Ionization
The interaction of matter with high-intensity laser radiation can lead to the absorption of multiple photons. For ultrashort laser pulses, the sudden deposition of large amounts of energy creates non-equilibrium states that rapidly evolve in time. This project explores the outcome of the interaction of intense, femtosecond duration laser pulses with the surface of liquid water. In analogy to the well-known process of Matrix-Assisted Laser Desorption/Ionization, we anticipate that water can be ejected from the bulk and form a plume that carries with it any molecules and ions that were dissolved in the liquid. The absorption depth of water for high intensity pulses is very small, on the order of one micrometer, so that only a thin surface layer of water is ejected. In this project, we use non-equilibrium molecular dynamics simulations to simulate the laser ablation of analyte molecules suspended in a liquid water bath. Both coarse-grained models using the CHARMM molecular dynamics solver and fully atomistic simulations will be performed to probe the underlying fundamental physical processes driving the desorption-ionization process and to characterize the ejected plume composition. This project has important applications for mass spectrometry, which is a frequently used analytical method in research labs and in the field. Advances could lead to smaller and more compact instruments, as well as tools with unique capabilities.This research will advance Brown's position in the field through high-impact publications and by generating preliminary data that will lead to external funding to support collaborations with experimentalists from the Chemistry Department.
PI: Jesse Ault, Assistant Professor of Engineering
Life Beyond Earth: Determining the Habitability of Exoplanets
Our understanding of the universe has been revolutionized by the detections of exoplanet worlds beyond our Solar System. Specifically, these detections have informed us about the diversity and quantity of planetary systems in existence, how planets evolve, and where extraterrestrial life may exist beyond Earth. Yet these exoplanet worlds are sufficiently far away from the Earth that only minimal information on these worlds is available (e.g., mass, density, atmospheric composition). For this project, we will demonstrate that the expertise within DEEPS of modeling the linked tectonic, volcanic, and atmospheric evolution of planetary bodies coupled with the expertise of Physics in exoplanet/stellar observations can be used to reliably infer surface properties of exoplanets and identify environments capable of sustaining life. We will use the preliminary results of this project to apply to available external funding sources throughout NASA and NSF.
PI: Alex Evans, Assistant Professor of Earth, Environmental, and Planetary Sciences
Co-PIs: Stephen Parman, Associate Professor of Earth, Environmental, and Planetary Sciences; Daniel Ibarra, Assistant Professor of Earth, Environmental, and Planetary Sciences and Environment and Society; Gregory Tucker, Professor of Physics
Fiber-Optic Load Sensor for Investigating Laboratory Earthquake Processes
We propose to adapt a newly designed fiber-optic sensor to dramatically improve the resolution of stress measurement in our high-pressure deformation apparatus at high temperatures. Pilot data acquired at ambient temperature demonstrate the efficacy of the approach; here we request funds to test a modified design for experiments at pressures and temperatures where earthquakes occur in plate boundary subduction zones. Subduction zones host Earth’s largest and most damaging earthquakes and tsunamis. While characterization of earthquakes and slip behavior along subduction zones has advanced rapidly, our understanding of the underlying processes that control mechanics lags behind. The roles of pressure and temperature are central to this problem. Currently, the stress resolution in the apparatuses capable of reaching these conditions is not high enough to resolve the transient behavior that is key to understanding the relevant processes. Thus, models of these processes rely on data acquired at much lower pressure, where in situ devices can be incorporated in the experimental design. With our new fiber-optic cell, we have demonstrated the ability to improve stress resolution by approximately a factor of 30 (at ambient temperature) relative to other apparatuses capable of deforming samples at relevant pressures. With successful pilot data demonstrating the application of the fiber-optic sensor at high pressure temperature conditions, we will be poised to write competitive proposals to the NSF Geophysics panel and a new NSF initiative to study earthquake processes in subduction zones, and leverage continued support for our NSF funded rock deformation facility.
PI: Greg Hirth, Professor of Earth, Environmental, and Planetary Sciences
Synthetic Modeling Studies of the Repair of Iron-Sulfur Clusters in Redox Signaling
Proteins containing [Fe-S] clusters carry out multiple crucial biological functions, including gene regulation. This proposal addresses redox sensing by [Fe-S] clusters via a synthetic modeling approach. By studying the geometric and electronic structures, reactivity, and bonding properties of discrete biomimetic model complexes, we seek to understand strategies used in [Fe-S] regulatory proteins to battle against oxidative and nitrosative stress at the molecular level. Specifically, the goal of this Seed proposal is to understand the mechanisms by which a pH and redox sensor, mitoNEET, activates its function of [Fe-S] transfer in response to oxidative stress. The human mitoNEET protein has a unique asymmetric [2Fe-2S] cluster ligated by three cysteines and one histidine. MitoNEET transfers its own [2Fe-2S] cofactors to its partner apo-proteins when the [2Fe-2S] center is oxidized (e.g., under oxidative stress) and the His ligand is protonated. However, it is not well understood what causes this redox-dependent cluster transfer upon protonation and how the [Fe-S] core is transferred without complete disassembly. In our preliminary studies, we developed a novel synthetic method to prepare site-differentiated [2Fe-2S] clusters bearing a neutral N-donor ligand as a model system for the unstable mitoNEET intermediate en route to cluster transfer. Our proposed studies include the elucidation of the electronic structures of mitoNEET models to understand how the presence of a neutral N-donor ligand influences the neighboring Fe-S(sulfide) and Fe-S(thiolate) bonds. We will also examine the feasibility of [Fe-S] transfer from mitoNEET analogs to another chelate without disassembly of the [Fe-S] core.
PI: Eunsuk Kim, Associate Professor of Chemistry
Using resistively detected microwave resonance to study quantum material and develop 2D material-based quantum-bit
This proposal has two main focuses: (i) develop the ability to directly probe and characterize spin excitations in 2D material structures using resistively detected microwave resonance techniques; (ii) develop necessary experimental schemes to couple microwave to 2D material-based quantum-bit (qubit) and realize fundamental qubit control. Observation of microwave resonance in 2D material structures has remained elusive since the discovery of graphene almost 2 decades ago. Recently, we have demonstrated for the first time that microwave resonance in 2D material structure can be resistively detected. This experimental breakthrough is achieved by introducing spin-orbit coupling to a flat energy band of graphene moiré structures. The ability to coupling microwave radiation to the spin structure of 2D material will establish a powerful addition to the toolbox of condensed matter research, which will be widely adopted by research groups worldwide. At the same time, this technique could enable experimental control on quantum-bit based on 2D material structures, which is the essential ingredient for various schemes of quantum computation. The support of the Seed award will allow us to achieve three main outcomes in a reasonable time frame: (1) we will build a microwave setup in my research lab at Brown University; (2) we will further develop the microwave resonance technique by defining the parameter range for optimal operation, which will establish resistively detected microwave resonance a powerful tool for condensed matter research; (3) we will demonstrate coupling between microwave and electrons in the quantum dot device geometry and perform basic qubit controls.
PI: Jia Leo Li, Assistant Professor of Physics
Co-PI: Vesna Mitrovic, Professor of Physics
Statistics of Classical Nonlinear Dynamics by Quantum Computation
We will use quantum computers to find the statistics of classical nonlinear dynamical systems far more efficiently than is possible with classical computers. Dynamical systems of interest range from those describing chemical reactions to climate models. We will use high quality trapped-ion based quantum computers developed by IonQ, Inc. (we have received time on their machines through the IonQ research credit program). To take full advantage of this resource we are requesting seed funding to support a PhD student based in the Departments of Chemistry or Physics to work on implementing quantum linear algebra algorithms on the IonQ computer to complete the project. We will then be in a strong position to apply for external funding, helping to fulfill Brown’s ambition to develop strengths in quantum information science.
PI: John Marston, Professor of Physics
Co-PI: Brenda Rubenstein, Associate Professor of Chemistry
Engineering a new generation of bio-inspired autonomous underwater robotic sensors
Metachronal swimming is a propulsive gait allowing small aquatic organisms of O(10) mm to perform up to 1000-meter-long vertical migrations in the ocean. By sequentially beating appendage pairs and modulating the forces on their body while swimming, marine crustaceans (e.g., krill) can effectively sustain long-distance migrations. However, the mechanism of metachronal swimming is poorly understood due to the small size of the organism and the lack of force and flow field measurements. In this project we will combine standard experimental techniques in fluid mechanics and unique robotic models to answer fundamental scientific questions regarding thrust generation and flow-structure interactions. Using our unique metachronal robotic model, we reproduce the swimming kinematics of Antarctic krill, an abundant animal species of Earth. We will combine flow visualization with force measurements to provide a quantitative evaluation of the links between swimming kinematics, force production, and vortex dynamics during forward swimming. Our results will lay the foundation for the development of a new generation of underwater robotic platforms that can effectively perform essential underwater activities, including exploration, targeted sensing, and filtering of micro-particles.
PI: Monica Martinez Wilhelmus, Assistant Professor of Engineering
Enabling mobility in terahertz networks
One of the challenging aspects of engineering a wireless network at very high frequencies is to determine how to maintain a high-quality link even when the receiver is in motion. In existing 4G wireless systems, which operate at lower frequencies below 6 GHz, this problem is addressed by using quasi-omnidirectional broadcasts. If the signal is broadcast in all directions, then a receiver is always within the broadcast sector of the base station or tower, and can move freely without worrying about losing the connection. However, at higher frequencies, particularly those above 100 GHz that are under increasingly intense investigation for use in future (beyond 5G) systems, this problem is much more challenging. At these high frequencies, connections will need to rely not on omnidirectional broadcasts, but instead on very directional pencil-like beams. To maintain a link even when the receiver is mobile, this beam must be dynamically steered so that it continuously points in the correct direction. To date, no realistic solution to this challenge has been identified; as a result, beam steering is now a primary concern in the design of systems that will operate in this frequency range. In the proposed research program, we will explore the use of a space-time-modulated metasurface, a micro-antenna array subject to a complex temporal and spatial modulation pattern, to provide this beam steering functionality. If successful, our results will establish a new paradigm for the design of terahertz wireless links.
PI: Daniel Mittleman, Professor of Engineering
Social Video Verification from Multiple Cameras
Deepfakes can spread misinformation, defamation, and propaganda by faking videos of events, like public speaker or protests. We assume that future deepfakes will be visually indistinguishable from real video and will also fool current deepfake detection methods. As such, we posit a social verification system that instead validates the truth of an event via a set of videos captured by multiple different people. To confirm which, if any, videos are being faked at any point in time, we propose to embed videos within the model space of learned generative deep neural networks and enforce multi-camera constraints that factor the change in appearance across camera views. Then, we propose to check for inconsistent appearance across videos using graph analysis, where each camera is a node and where edge weights are formed from the embedding distance. Initially, we will focus on facial appearance as it is a high-value fake target; then, given future funding generated from this seed, we will expand our remit to cover human body and multiple human interaction appearance. Overall, this project combines socially responsible computing ideas with new techniques in multi-camera appearance modeling to provide new tools to combat deepfakes.
PI: James Tompkin, Assistant Professor of Computer Science
CO2 Capture by Conversion: Carbon-based Chemicals from Carbonate Reduction
A dream technology would capture CO2 directly from the air and use it as a feedstock to produce renewable carbon-based fuels and chemicals, rather than relying on fossil fuels. Nearly all approaches to date have separated CO2 capture and CO2 conversion into two distinct steps, but the compounding inefficiencies make the process impractical. This proposal targets a key step in the CO2 capture/conversion processes by studying catalytic approaches to carbonate reduction. CO2 can be easily captured by an alkaline solution and by converting CO2 to a carbonate, but this carbonate is difficult to reduce. In this project, we will first react (saturate) atmospheric CO2 in an alcoholic alkaline solution to produce an alkylcarbonate, and will then reduce this carbonate via either electrochemical or chemical reduction method. Aided by computational design, we will prepare and study Cu-based nanoparticle catalysts to reduce the carbonate to an active form of carbon. Our goal is to demonstrate a scientifically viable catalytic approach to bridge CO2 capture and conversion. The research will provide promising solutions to climate change and sustainability issues associated with CO2 emissions.
PI: Shouheng Sun, Vernon K. Krieble Professor of Chemistry, Professor of Engineering
Co-PI: Andrew Peterson, Associate Professor of Engineering
Life and Medical Sciences
Development of a Massively Parallel Reporter Screen in Whole Fish
The breeding program that generates farm raised Atlantic Salmon is in its 17th generation. A growing awareness of the environmental impact of aquaculture has driven regulation reducing the use of outdoor pens. Here, we propose the application of state-of-the-art genomic technology to animal breeding to bring fish to market faster and reduce the use of outdoor pens. A successful breed/strain contains naturally occurring genetic variations that increase or decrease the levels of genes that positively influence growth, resistance to disease/cold, and physio-metabolic qualities such as adiposity. While many genes influence salmon commercial appeal, it is clear that increased growth hormone (GH) production is desirable as it reduces growth time. GH, along with antifreeze proteins (AFP) has been the target of all transgenic aquaculture lines developed for research purposes in the past 30 years. Here, we propose technology that will screen every possible variation in the salmon growth hormone promoter using a high throughput massively parallel reporter assay. Briefly, this technique will determine the effect of every possible variant that could occur naturally and measure how it a) affects growth hormone level and b) retains proper growth hormone expression (i.e. remains expressed only in the pituitary gland). This proposal represents the first proof of principle application of a massively parallel reporter system in a model organism (zebrafish). Variants that increase GH in the reporter system and transgene will be tested in a “salmonized’ zebrafish.
PI: William Fairbrother, Professor of Biology
Co-PI: Jessica Plavicki, Manning Assistant Professor of Pathology and Laboratory Medicine
How does locus-specific DNA amplification override DNA re-replication controls in the genome?
The cell utilizes multiple controls to ensure that each origin of replication (ORI) is activated only once per cell cycle. When these controls are overridden and an origin fires more than once, local DNA amplification results. DNA amplification is a hallmark of cancer, but the mechanism of the initiating events that drive re-replication is unknown and cannot be studied in cultured cancer cells. Instead, we are using the fly Sciara that is one of only two known examples where locus-specific intrachromosomal DNA re-replication results in DNA amplification at 18 “DNA puffs” in larval salivary gland polytene chromosomes as a normal developmental event. We have focused on DNA puff II/9A, the most highly amplified of the DNA puffs. We have mapped the II/9A ORI of re-replication, a DNase hypersensitive site (DHS) 600 bp upstream and bent DNA between the DHS and the ORI. Injection of the steroid hormone ecdysone induces premature DNA amplification. Our ChIP and CUT&RUN experiments revealed that the ecdysone receptor (EcR) binds to the DHS that we hypothesize loops back to contact the ORI since EcR co-immunoprecipitates the origin recognition complex that is part of the pre-replication complex bound to the ORI. We propose to develop a new method using CRISPR for site-directed mutagenesis for insertion or deletion of large stretches of DNA to test if deletion of the DHS abrogates DNA amplification. The results will be of significance to the fields of DNA replication, cancer, and genomic engineering (“editing”), underscoring Brown’s support of conceptual and technical advances.
PI: Susan Gerbi, George D. Eggleston Professor of Biochemistry
Axon guidance through changes in growth cone membrane potential
In order to produce a functioning nervous system, neurons must form precise connections with each other during embryonic development. The guidance of growing axons to their correct targets is central to sculpting neuronal connectivity, and understanding this process is critical, as neuronal miswiring can cause neural circuit dysfunction and disease. Our project investigates if molecular cues instruct axon pathfinding by triggering changes in the axonal membrane potential. We propose to employ and improve our cutting-edge, genetically encoded voltage sensors to monitor the membrane potential of axons in response to various attractive and repulsive guidance cues, with the goal of identifying patterns of membrane de- or hyperpolarization that dictate the axonal response to attractants versus repellants. This will lay the foundation for a long-term plan to investigate the causal relationship between guidance cues, axonal membrane potential, and axon steering. Our work will uncover fundamental mechanisms of axon guidance and neural circuit assembly, which is essential for understanding disorders of brain wiring and developing therapeutic approaches for the restoration of damaged neuronal connections after physical injury or onset of neurodegenerative disease.
PI: Alexander Jaworski, June G. Zimmerman Associate Professor of Brain Science
Co-PI: Ahmed Abdelfattah, Robert J. and Nancy D. Carney University Assistant Professor of Brain Science
Establishing a Drosophila model for opioid self-administration
The U.S. is in the midst of an opioid epidemic and overdose crisis, which has only been exacerbated by the COVID-19 pandemic. It is imperative that the health community have access to the most effective treatments to help solve this epidemic. However, effective treatment development requires a better understanding of the neurobiology of opioid use and dependency. The lasting physiological effects of opiates on reward memory circuits contribute to cravings for the drug and change the brain’s response to other drugs of abuse. Opiate drugs bind to opioid receptors (ORs) in the brain, hijacking a complex endogenous neuromodulatory system. In mammals, µ opioid receptors (µORs) are the key molecular targets for the biological effects of clinically useful and abused opioids. The sheer number and heterogeneity of neurons within reward circuits, combined with their elaborate connectivity, has prevented a deeper understanding of the identity of µOR expressing circuits. A small but sophisticated brain and impressive array of neurogenetic tools for in vivo analysis have proven the fruit fly, Drosophila melanogaster, to be an ideal model for discovery of novel mechanisms underlying the effects of drugs of abuse on the brain. Here we propose to establish Drosophila as an effective model to understand the neural and molecular mechanisms underlying the motivation to seek the high-potency synthetic opioid fentanyl. Our goal is to use a functional neurogenetic approach to identify the Drosophila µOR and map the neural circuits through which this receptor is eliciting fentanyl-induced behavioral responses.
PI: Karla Kaun, Associate Professor of Neuroscience
Identification of LRRC15 as a novel restriction factor for SARS-CoV-2
SARS-CoV-2 infection relies on the ACE2 receptor for its cellular entry. Although cellular entry of the virus is the primary target for antiviral therapeutics, it is understudied how entry of SARS-CoV-2 is regulated. Here we show that Leucine-rich repeat-containing protein 15 (LRRC15) is a novel restriction factor for SARS-CoV-2. Using a focused CRISPR activation screening targeting all known cellular surface proteins, we identified LRRC15 as a cellular restriction factor that binds to Spike protein of SARS-CoV-2. Expression of LRRC15 in SARS-CoV-2 permissive cell lines strongly inhibits the infectivity of Spike-pseudo-typed VSV but not G-pseudo-typed VSV, indicating the restriction activity is coronavirus-specific. The binding between Spike and LRRC15 is confirmed by a cell-free binding assay. In this proposal, we will examine the physiological role of LRRC15 in restricting SARS-CoV-2 infection with two specific aims. Aim 1, we will define the specificity of the restriction activity of LRRC15 across human coronaviruses including SARS-CoV-1, MERS, and seasonal coronaviruses. Aim 2, we will test whether LRRC15 is associated with severity of disease progress, robustness of viral replication, and asymptomatic/symptomatic disease outcome in patients using publicly available datasets. This study will provide one of the first human cellular restriction factors regulating SARS-CoV-2 infection and shed an insight into novel design for therapeutics.
PI: Sanghyun Lee, Assistant Professor of Molecular Microbiology and Immunology
Targeting purinergic receptors in synaptic glia to treat ALS
Amyotrophic Lateral Sclerosis (ALS) is an adult-onset neurodegenerative disease that causes paralysis and death within 5 years of diagnosis. Although the disease has been clinically recognized for over 140 years, effective therapies for ALS have yet to be developed. Riluzole and Radicava (Edaravone), the only therapies approved for ALS, are minimally effective, only extending life by several months. A hallmark of ALS is early and progressive destruction of the neuromuscular junction (NMJ), the peripheral synapse that controls all skeletal muscles and thus voluntary movements. Development of treatments that target the NMJ have been hampered by the paucity of information about molecular mechanisms critical for NMJ maintenance and repair. To address this gap, our lab has focused on the molecular composition of synaptic glial cells of the NMJ, which have been largely overlooked. We have discovered that these cells express three purinergic receptors with well-characterized roles in synaptic maintenance in the central nervous system. In this work, we will test the hypothesis that modulating the activity of these purinergic receptors, using FDA-approved pharmacological agents, will mitigate NMJ degeneration in a mouse model of ALS. The preclinical data arising from this work may set the stage to target purinergic receptors to treat patients suffering with ALS.
PI: Gregorio Valdez, GLF Translational Associate Professor of Molecular Biology, Cell Biology and Biochemistry
An extracellular Prion-like protein is essential for fertilization
Prions are a type of protein domain that can trigger normal proteins to fold abnormally. Human proteins with domains that resemble yeast prions form protein aggregates that cause cell death in neurodegenerative diseases. Yet, these same domains are able to form dynamic liquid-like droplets that contribute to the formation of membraneless organelles including numerous cytoplasmic and nuclear compartments. We recently learned that Bindin from sperm of a sea urchin has two prion-like domains, is secreted, and is essential for fertilization. Extracellular prions are very unusual (and no extracellular eukaryotic prion-like proteins or prion-like phase separated assemblies have been described in detail). These prion-like domains have highly variable sequences between species, thought to be species-specific recognition elements. We will dissect the prion-like domains and test their role in sperm-egg interaction and species specificity by in vitro egg interaction. Three features make this work of high impact: 1) Is the prion-like domain essential for its function? We currently know only that the Bindin product is essential. 2) Does the prion-like domain confer species-specific sperm-egg recognition? Production of the prion-like domain and modifications thereof will be used to test egg interactions species specifically. 3) Does the prion-like domain self-assemble into extracellular liquids, gels, or aggregates – the spectrum of states seen for intracellular prion-like domains? This preliminary work will have high impact in several fields of biomedical research and clinical application, breaking new ground in the molecular mechanism of critical steps in fertilization and describing the unexplored atomic details of this extracellular assembly.
PI: Gary Wessel, Professor of Biology
Co-PI: Nicolas Fawzi, Associate Professor of Molecular Biology, Cell Biology and Biotechnology
Life, Medical and Physical Sciences
Development of Quantum Magnetic Tunneling Junction Sensor Arrays for Magnetoencephalography (MEG)
We aim to develop a revolutionary quantum magnetic gradiometer designed to non-invasively register femtoTesla (fT) scale magnetic fields from the human brain and examine its operating characteristics during simple voluntary movements and visual stimulation. The sensor, with its miniaturized size, will substantially exceed the spatial resolution of existing systems, operate at room temperature, will not require expensive magnetic shielding, can be used untethered, thus, in the field, and the expected system will have a far lower initial purchase price and lower maintenance costs than available magnetoencephalographic (MEG) systems. These features should expand the utility, accuracy, and accessibility of magnetic field recording technology for human neuroscience applications to advance our understanding of human brain function in health and disease.
PI: Gang Xiao, Professor of Physics, Professor of Engineering
Co-PI: Jerome Sanes, Professor of Neuroscience
Vector beam pulse oximetry
The onset of COVID-19 has made the rapid and accurate detection of irregular oxygen saturation levels important in curbing the number of resulting deaths. As a result, the past year has seen significant interest in traditional photoplethysmography (PPG) technology, namely pulse oximeters, to monitor oxygen saturation levels. Moreover, there has been an increased demand for smartwatches and other wearables that can accurately carry out on-demand PPG measurements. However, several studies have reported that this optical technique overestimates the actual oxyhemoglobin saturation in patients with darker skin tones, leading to silent hypoxia and a potentially disproportionately higher number of deaths for black and brown patients, in particular. This work will focus on developing a novel PPG technique to mitigate the issue of skin tone, and other related skin-based confounding effects such as wrinkles and tattoos, using an optical polarization vector beam. Compared to other algorithms that exploit polarization to suppress skin effects and increase accuracy, our approach enables multiple polarization measurements in parallel, thereby offering increased speed.
PI: Kimani Toussaint, Professor of Engineering
Safety, feasibility, and acceptability of MDMA-assisted therapy for the treatment of co-occurring posttraumatic stress disorder and alcohol use disorders in combat veterans
Co-occurring PTSD and alcohol use disorder (PTSD-AUD) is common following combat and associated with more severe symptomatology, increased suicidality, and poorer response to treatment than either disorder alone. Available PTSD-AUD treatments effectively treat only a fraction of people who engage in them for adequate dose and duration, leading to growing interest in alternative medications, including psychedelics. The combined neurobiological effects of MDMA increase compassion, reduce defenses and fear of emotional injury, and enhance communication and introspection, making MDMA-AT especially useful for treating PTSD-AUD. This pilot trial will be the first to assess feasibility and acceptability of MDMA-assisted psychotherapy (MDMA-AT) in veterans with combat-related PTSD and AUD (N=20) and will result in a new interdisciplinary collaboration at Brown. Participants will be recruited via social media and clinician referrals and will complete an initial screen and baseline appointment including informed consent. Eligible participants will receive MDMA-AT, including three Experimental Sessions with MDMA administration that will be conducted under established protocols. Follow-up data will be collected at post-treatment and at one-month. This project will allow us to: 1) assemble a research team including the training of two MDMA-AT clinicians, 2) determine the feasibility of recruitment, 3) determine the acceptability of and safety of MDMA-AT, 4) provide preliminary evidence of the effects of MDMA-AT, and 5) refine study procedures in preparation for a fully powered RCT to test the effectiveness of MDMA-AT for PTSD-AUD. This collaboration will help to position Brown at the forefront of psychedelic research for common and impairing mental health problems.
PI: Carolina Hass-Koffler, Associate Professor of Psychiatry and Human Behavior and Associate Professor of Behavioral and Social Sciences
Co-PI: Erica Eaton, Assistant Professor of Psychiatry and Human Behavior (Research), Assistant Professor of Behavioral and Social Sciences (Research)
Observational study of the safety, accuracy and usability of digital diagnosis apps in primary care and for TIA and stroke patients
Patients commonly search their symptoms and diseases online, and mobile phone apps for digital diagnosis (“Symptom Checkers”, SC) are used by >40 million US patients annually. However there is minimal evidence from real patient use in the community on accuracy of diagnosis or triage, patient safety, or usability. This research builds on collaborations between Brown Center for Biomedical Informatics, The Rhode Island Hospital (RIH) Emergency Department (ED) and Brown Medicine to research the role and potential impact of symptom checker (SC) apps used by patient seeking urgent primary care, and the performance of SCs and new algorithms for diagnosis of transient ischemic attacks (TIA) and stroke. AIM 1 will extend an evaluation of a leading SC from Ada Health, with use by 200 patients requesting urgent care appointments at Brown Medicine, including a usability questionnaire, prior to their appointment. Reviews of the symptom data and results from the App and the physician who sees the patient will allow comparison of diagnosis and triage. AIM 2 will analyze the accuracy of symptom checkers including Ada and develop new algorithms using 2 data sets of symptoms of patients presenting with TIA or stroke - high risk diseases with hard to recognize symptoms, requiring urgent treatment. Data sets include 1800 patients admitted with suspected TIA to the clinical observation unit, RIH, and 100,000 patient consults with Ada App, and possible stroke diagnosis. We will study diagnostic performance of multiple SCs and new algorithms including effects of age and gender, Quick patient recognition of stroke and prompt arrival in the ED should reduce the current high morbidity and mortality.
PI: Hamish Fraser, Associate Professor of Medical Science
Teaching High School Students about Autonomous Aerial Robots
The aim of this proposal is to test the hypothesis that we can prepare high school teachers to teach students about autonomous aerial robots on their own, at scale by 1) providing a project-based curriculum targeted at the high school level on an open-source low-cost autonomous robot with few infrastructure requirements; 2) providing remote professional development workshops for teachers; and 3) pairing teachers with Brown students familiar with the curriculum who will provide help and technical support. We will study the interactions between teachers and curriculum materials, tools, and Brown students who facilitate the learners' conceptual development, and what characteristics our online PD and remote support give rise to these interactions. Our work will assess each of these three interventions by assessing teacher content knowledge as well as self-efficacy. We will also assess the effectiveness with which we can engage students in both urban and suburban districts through hands-on remote learning curricula that emphasize physical hardware, in the hands of the students as well as via remote laboratories. This work has the potential to directly benefit students in Rhode Island, consistent with President Paxson's commitment to Providence public schools. Moreover this funding will provide critical preliminary work enabling us to apply for follow-on funding for larger expansions from NSF and industry resources to grow our project to a nationwide and international effort to teach students about autonomous robotics.
PI: Stefanie Tellex, Associate Professor of Computer Science
Co-PI: Diane Silva Pimentel, Senior Lecturer in Education
Finding the Physics that Matters in Astrophysical and Astro-Particle Analyses with Interpretable Machine Learning
As more and more analyses depend on machine learning, physicists need to understand the biases induced in their models by the training data they use. In many situations they face a tradeoff between two types of data: (1) abundant but low-resolution, synthetic, or otherwise approximate data, and (2) scarce but high-resolution, high-fidelity, or otherwise more realistic data. The ideal would be to correct the biases in the abundant data so that it is more like the scarce data in the ways that affect the predictions of the machine learning models trained on that data. If done, then scientists would have access to higher quality, abundant data. The problem is that, even though it is easy to tell that models trained on each type of data disagree in their predictions, it is hard to tell which aspects of the input are leading to that disagreement. Our proposal is to create a software framework for identifying these key causes of differences.
PI: Stephon Alexander, Professor of Physics
Co-PIs: Stephen Bach, Assistant Professor of Computer Science; Ian Dell’Antonio, Professor of Physics; Richard Gaitskell, Hazard Professor of Physics; Jonathan Pober, Assistant Professor of Physics
Reverse Engineering the Synaptic Cleft - the Search for Quantum Information Processing in the Brain
The interdisciplinary team proposes to test the idea that the fundamental principle of a complex brain operation is quantum processing involving nuclear spins of phosphorus as a neural qubit. This idea originates from a reputable theoretical physicist M. Fisher, UCSB. He identified the hypothetical Posner molecule as one that can protect neural qubits very long times and thereby serve as a working quantum-memory. Our novel approach involves harnessing the properties of nuclear spins to study quantum information processing (QIS) in the brain by reverse engineering specific polymers and biomolecules to provide sufficiently long coherence times required for quantum processing. This is orthogonal to the UCSB’s approach that focuses on the search of Posner molecule. The team members are highly complementary and have a well-established prior record of collaborations. Palmore will synthesize polymer based biomaterials with appropriate nuclear spin species, while Mitrovic and Walsh will use the nuclear magnetic resonance (NMR) technique to test possible coherence propagation and test whether such bio-materials can be used as a quantum register to process information. The team has identified the appropriate synthesis and patterning of phosphates into specific isotopically labeled and DNA nanostructure. They have also designed the NMR experiment to test the quantum nature of neural signal transmission, and NMR experiments to test nuclear spin coherence. Our long-term goal is to identify essential biomaterial properties required for QIS and quantum signal transmission using nuclear spins of phosphorus. The ultimate goal is synthesis of artificial neural synapses and memory registers.
PI: Vesna Mitrovic, Professor of Physics
Co-PIs: Tayhas Palmore, Elaine I. Savage Professor of Engineering, Professor of Chemistry; Edward Walsh, Assistant Professor of Neuroscience (Research)
Using Artificial Intelligence to Search for New Physics Underground, on the Ground, and in the Sky
In the past few years, significant developments in high-power, massively parallel computing, made in part possible by the advancement of fast GPUs, FPGAs, and specialized processors, took artificial intelligence (AI) to a qualitatively new level, making it a valuable tool for scientific research. Some of the AI methods, such as supervised and unsupervised machine learning (ML) using deep neural networks, are now being widely deployed in large scientific experiments in particle and astroparticle physics, both for data reconstruction and for unraveling subtle signals over otherwise overwhelming backgrounds. Typical data from these large detectors, organized in a series of “events,” i.e., snapshots of the detector triggered by a certain, interesting activity, naturally allow for massive parallel processing of the data and for identifying characteristic patterns within. We propose to utilize advanced AI methods and a combination of supervised and unsupervised ML algorithms to look for unusual patterns in the data of experiments underground, on the surface of the Earth, and in the sky. More specifically, we will focus on unconventional experimental signatures of new physics in the Brown-led LUX/LZ detectors at the Sanford Underground Research Facility by exploring new methods for identifying heterogenous particle recoil signatures involving both nuclear and electron recoil components, at the CMS experiment at the Large Hadron Collider at CERN by looking for jets with unconventional structure or patterns, and in the sky using forecasting weak gravitational lensing data from the Square Kilometer Array to discern the presence of dark matter substructure using time dependent spatial correlations.
PI: Greg Landsberg, Thomas J. Watson, Sr. Professor of Physics
Co-PIs: Richard Gaitskell, Hazard Professor of Physics; Savvas M Koushiappas, Associate Professor of Physics
Responsive Hydrogel Based pH Regulation of Cancer Tumor Microenvironment to Reduce Metastasis
Cancer cells are known to create acidic extracellular environments through the excretion of acid byproducts due to irregular metabolic pathways. This unusually acidic extracellular tumor microenvironment compared to healthy tissues may be targeted through cancer therapies. Counteracting the pH of the tumor microenvironment in in vivo mouse models by ubiquitous bicarbonate delivery has shown promise. Currently, an effective method of locally regulating the pH of the tumor microenvironment to reduce cancer progression due to acidosis does is lacking and our research aims to fill this important need by developing a responsive hydrogel pH regulating system by demonstrating its efficacy in cancer treatment. We aim to develop a novel biocompatible pH regulating hydrogel that reduces cancer metastasis and invasion by continuously counteracting the acidosis of the extracellular space. We will conduct in vitro experiments to test proliferation, motility, and invasion of MDA-MB-231 breast cancer cells when exposed to our novel hydrogel. Completion of our study will allow further research into targeted delivery of pH regulating hydrogels in vivo as well as new studies of subcellular cancer cell mechanisms that can be regulated through pH control.
PI: Vikas Srivistava, Assistant Professor of Engineering
Syntheses of Atom-Precise Gold Nanoclusters with In Situ Catalytic Active Sites for Hydrogen Activation and Electrocatalysis
Nanoparticles display properties that are different from bulk materials and in particular can be excellent catalysts for important chemical reactions. However, because of the size and surface inhomogeneity, the mechanisms of catalytic reactions by nanoparticles are often challenging to be deciphered. This project aims at advancing nanochemistry through the syntheses of novel ligand-protected and atom-precise gold nanoclusters with uncoordinated sites, which can serve as well-defined in situ activation centers for catalysis. While there have been major advances in the syntheses of atom-precise nanoclusters, information about the active sites of these nanoparticles in catalytic applications are still challenging to obtain because often times the ligands need to be removed to create active sites that can introduce uncontrolled structural changes. The motivation of this project is to address this challenge by synthesizing ligand-protected nanoclusters with uncoordinated atoms, that can be used as in-situ active sites. The first goal of the project is to find new ligands that allow the syntheses of gold or bimetallic gold nanocluster with precisely-defined size and structure. The second goal is to explore their catalytic properties and obtain preliminary data about hydrogenation reactions and electrocatalysis.
PI: Lai-Sheng Wang, Jesse H. and Louisa D. Sharp Metcalf Professor of Chemistry
Life and Medical Sciences
Defining Neuron-glial Synaptic Interactions in Health and Alzheimer's Disease
If current prevention and intervention strategies remain the same, one in three of us will be diagnosed with Alzheimer’s disease (AD) in our lifetime. Therefore, it is critically important to discover new, effective treatments, and the key to doing so is to fully understand how AD develops. Unfortunately, this understanding is limited by the absence of an appropriate humanized model system and the deficiency in general knowledge to guide an experimental path forward are the major reasons for this gap. To tackle such a challenge, our two research teams have combined our distinct expertise and devised original techniques based on stem cell technology and computational genomics, to study the neuron-glial communications that become disrupted in AD and aged brains. Specifically, the objective of this pilot project is to develop an integrated platform to discover the nature of direct synaptic interactions between neurons and oligodendroglia in both healthy and diseased individuals. The work proposed here represents a novel research horizon for the field, ultimately aimed at inspiring a new therapeutic logic for AD and relevant brain aging disorders. We will leverage our multidisciplinary expertise uniquely established at Brown to couple cellular reprogramming methods with modern genome scanning and editing techniques. Our preliminary data have provided the very first evidence supporting the neuron-OPC synaptic mechanism as an emerging therapeutic target for further translation. Our approaches are amenable to contemporary studies of neurodegeneration and aging beyond AD and we hope to extend our collaboration with Brown’s vibrant faculty to further synergize our discoveries.
PI: Yu-Wen Alvin Huang, GLF Translational Assistant Professor of Molecular Biology, Cell Biology and Biochemistry
Co-PI: Ashley E. Webb, Richard and Edna Salomon Assistant Professor of Molecular Biology, Cell Biology and Biochemistry
Structure and Post-Translational Modifications of Candida Transcription Factors and their Impact on Phase Separation
The ability of macromolecules to undergo liquid-liquid phase separation (LLPS) is now recognized as underlying a number of key biological phenomena. Our studies have revealed that transcriptional regulation in the pathogenic fungus Candida albicans is controlled via LLPS, as multiple transcription factors can come together to form phase-separated condensates that are critical to the regulation of transcription networks in this species. This mechanism has been directly linked to the presence of prion-like domains (PrLDs) in transcription factors (TFs) that promote their propensity to undergo LLPS and thereby form transcriptional hubs. In this proposal, we seek to determine how structural features and post-translational modifications (PTMs) alter the ability of TFs to undergo LLPS. A number of recent studies have shown that LLPS processes can be exquisitely sensitive to both PTMs and transient secondary structures that can impact phase separation. This is particularly relevant to fungal transcription networks where domains of unknown structure contribute to function and PTMs may enable cells to rapidly respond to external stimuli and activate an appropriate transcriptional response. We will therefore seek to define the structures and PTMs associated with the master TFs in C. albicans networks, and also examine how these features impact LLPS and transcriptional output by these factors. These findings are expected to have broad significance to the regulation of TF networks, and will provide fundamental insights as to how these features can regulate the properties of LLPS condensates.
PI: Richard Bennett, Professor of Biology
Co-PI: Nicolas Fawzi, Associate Professor of Molecular Pharmacology, Physiology and Biotechnology
Engineering Genetic Models for Translational Research in Autism and Schizophrenia
Schizophrenia is among the most devastating and enigmatic conditions affecting the human brain. It has a strong genetic component, and it shares neurodevelopmental components with other neuropsychiatric illnesses, such as autism. The project proposed here relates to study of 17q12 deletion syndrome, a highly-penetrant genetic mutation that confers susceptibility to both autism and schizophrenia. Using CRISPR/Cas9 genome editing and human stem cell methods, we will establish experimental models (mice and patient-derived stem cells) for 17q12 deletion syndrome. In validating our mouse model, we have identified a prominent and high-impact phenotype involving perturbation of forebrain development. Here, we will define the molecular mechanisms underlying these abnormalities in forebrain development. We will also establish a human iPSC resource with 17q12 deletion mutations. These 17q12 deletion studies will put us in a unique position to capitalize on human genetics and discover pathways critical to human forebrain development and neuropsychiatric disorders. The impact of this work will be to define new pathophysiologic mechanisms in schizophrenia (and other neuropsychiatric disorders), stemming from genetically-inspired, neurodevelopmental studies in patients and animal models. The research group involves a multi-disciplinary team that spans psychiatry, computational biology and molecular and cellular biology, and clinical and basic research, and includes two junior faculty (Moreno De Luca and Uzun) and a senior faculty (Morrow). Together, our efforts will provide important insights into the genetic underpinnings and the underlying mechanisms of 17q12 deletion syndrome as well as related developmental neuropsychiatric illness more broadly.
PI: Eric Morrow, Mencoff Family Associate Professor of Biology, Associate Professor of Neuroscience, Associate Professor of Psychiatry and Human Behavior
Co-PIs: Daniel Moreno De Luca, Assistant Professor of Psychiatry and Human Behavior; Ece Uzun, Assistant Professor of Pathology and Laboratory Medicine
Pulmonary Artery Endothelial Cell Phenotypes During Pulmonary Hypertension
Pulmonary hypertension (PH) is a devastating disease marked by endothelial cell (EC) dysfunction and vascular stiffness. While EC dysfunction is at the core of PH pathobiology, the PH EC phenotype is incompletely characterized and remains controversial. Current methods to study this gap source cells from end-stage patients, non-diseased cell lines, or outside of the pulmonary vasculature. Right heart catheterization is the fundamental diagnostic procedure in PH and is repeated throughout the disease course. We have shown that ECs from the balloons of pulmonary artery catheters can be harvested, propagated ex vivo and characterized and that the behavior and function of these cells is influenced by clinical traits and PH severity. We contend that ECs in severe PH display abnormal programmed cell death triggered by cell detachment, known as anoikis resistance. We will leverage this source of pulmonary artery ECs from living patients to define patient-, time- and substrate-based factors that influence EC phenotype. We will characterize the behavior and function of cultured ECs over the course of disease with established assays. We will measure and compare the response of these ECs on a biomimetic synthetic pulmonary vessel platform with variable stiffness and topography. We will identify the gene expression signature of cultured ECs and compare across samples and against that from primary cells. Our experiments will include ECs from patients with different forms of PH, diseased controls, and biological replicates from the same patients over time. Data derived will be used to further develop the project for a Multi-PI grant.
PI: Elizabeth Harrington, Professor of Medicine
Co-PIs: Corey Ventetuolo, Associate Professor of Medicine, Associate Professor of Health Services, Policy and Practice; Diane Hoffman-Kim, Associate Professor of Medical Science, Associate Professor of Engineering
Role of Senescence Associated Extracellular Vesicles in Radiation-Induced Pulmonary Fibrosis
Pulmonary fibrosis is a common side effect of thoracic radiotherapy; it limits treatment options for cancer patients and increases the risk for cancer metastasis to the lungs. This treatment modality is highly effective in killing mitotic cancer cells by damaging their DNA and inducing apoptosis. However, even low dose radiotherapy is capable of inducing cellular senescence in normal cells, and the accumulation of these senescent cells and their secretory phenotype described as key mediators of pulmonary fibrosis. Ionizing radiation also results in rapid activation and persistent expression of transforming growth factor-b (TGFb), a pleiotropic cytokine involved in extracellular matrix (ECM) remodeling. Yet, there remains a gap in our understanding of how radiation-induced senescence drives pulmonary fibrosis through TGFb-mediated ECM remodeling. Our recent study demonstrated that senescent cells deposit and crosslink ECM proteins altering the architecture and mechanics of the surrounding collagen-rich environment. Although senescent cells are relatively scarce in vivo, it is possible that their ECM modifications are transferred throughout the lung via senescence-associated exosomes (SA-EVs). Previous studies have shown SA-EVs can activate nearby fibroblasts promoting collagen matrix remodeling through TGFb. The proposed studies will investigate the role of SA-EVs in transferring TGFb-mediated ECM remodeling in the lung to promote radiation-induced fibrosis and malignancy.
PI: Michelle Dawson, Assistant Professor of Molecular Pharmacology, Physiology and Biotechnology
Life, Medical and Physical Sciences
Immunomodulatory Biomaterials for Treating Ischemia in Diabetic Models
Ischemic wounds occur when blood flow is reduced in a specific body area, leading to cell death and tissue damage. In diabetes, microvascular complications and unbalanced activation of the immune cells markedly compromise the repair from ischemic wounds, causing slower healing, development of chronic wounds and increased risk for infections.The overall objective of this proposal is to explore the mechanisms of wound healing in diabetes, by signaling of anti-inflammatory cytokines (CSF-1, IL4 and IL-13) via the JAK-STAT pathway, and to develop a novel treatment using preclinical models of non-healing diabetic ulcers. My preliminary data show that CSF-1, IL-4, and IL-13 regulate immune cells polarization and ischemic wound healing in monocyte cultures and non-diabetic animal models. With this proposal, we will elucidate the cytokines-driven regulation of the JAK-STAT signaling cascade in diabetes (Aim 1), we will deliver CSF-1, IL-4 and IL-13 from biomaterials to modulate the plasticity of monocytes isolated from the blood of diabetic rats and humans (Aim 2), and we will examine the healing of ischemic wounds in diabetic rats (Aim 3). This work will advance Brown’s position in the fields of immune engineering and wound healing therapy, will allow the PI to lay a solid foundation for expanding her research program in diabetes, and will be instrumental for attracting external funds. If successful, this project will identify suitable therapeutic targets for treating chronic wounds in diabetic patients, and will accelerate the translation to the clinic of novel immunomodulatory treatments for a patient population in great need.
PI: Fabiola Munarin, Assistant Professor of Engineering (Research)
Deep Learning Based on CT Angiography in Patient Selection for Endovascular Treatment of Large Vessel Ischemic Stroke
Stroke is a leading cause of long-term disability, and outcome in regaining functionality in areas supplied by anterior circulation large vessel is directly related to timely endovascular therapy (EVT). However, not all patients benefit from rapid intervention. CT perfusion is widely recognized as the selection tool to identify patients who will most likely benefit from reperfusion based on stroke core and penumbra size estimation as well as mismatch quantification. However, it is not routinely performed at many institutions in the United States and around the world. In this proposal, we propose to develop a fully automated artificial intelligence (AI) pipeline that identifies the images/series of interest, detect emergent large vessel occlusion and predicts immediate (e.g. the Thrombolysis in Cerebral Infarction [TICI[ score) and functional (e.g., modified Rankin score [mRS[) outcomes from EVT based on pre-procedure CT angiography. We will establish an end-to-end AI platform that interfaces with the Rhode Island Hospital (RIH) Picture Archiving and Communications Systems for real-time clinical use. The ability to predict immediate outcomes of EVT will affect management because proceduralists will be able to anticipate different reperfusion based on these predictions and adjust their treatment approach accordingly, while prediction of functional outcome assists in patient selection, resulting in improved outcome. We anticipate that the proposed project will further collaboration between the Department of Computer Science and the Department of Diagnostic Imaging, which is crucial in advancing Brown University's position in research on AI, machine learning and computer vision applied to the healthcare system and medical imaging.
PI: Ugur Cetintemel, Professor of Computer Science
Co-PIs: Harrison Bai, Assistant Professor of Diagnostic Imaging; Arko Barman, Assistant Teaching Professor, Rice University
Using ENDS to Reduce Harm for Low SES Cigarette Smokers
Smoking is the leading cause of preventable morbidity and mortality in the US, contributing to 480,000 deaths this year. Despite increasingly strong tobacco control, annual deaths are no different than 30 years ago and tobacco-related diseases continue to disproportionately burden individuals from lower socioeconomic populations. Prevention of use and cessation remain the primary goals. However, for those unwilling or unable to quit, substituting combustible tobacco smoking with electronic nicotine delivery systems (ENDS) can significantly reduce tobacco-related harms. We propose to randomize 50 socioeconomically disadvantaged smokers who are not planning to quit to three conditions: one of two ENDS conditions (4th generation nicotine salt pod e-cigarette [EC] or heat-not-burn tobacco [HNB]) or assessment only control. We will provide participants in the ENDS conditions with devices and 8 weeks of complimentary nicotine supplies and investigate the impact on cigarette use, dependence, full substitution (quitting cigarettes), and biomarkers of exposure, toxicity, disease, and inflammation. The results of this pilot project will elucidate the magnitude and clinical meaningfulness of these effects and inform the design of a fully-powered NIH R01 application comparing ENDS to gold-standard treatments. The multidisciplinary research team established by this Category 2 OVPR Research Seed Fund proposal spans the areas of clinical psychology, medicine, public health, and social epidemiology. This project will be one of the first to compare HNB to EC and investigate their harm reduction potential. Further, the study will fill a critical gap in the literature on the feasibility and acceptability of these procedures in socioeconomically disadvantaged populations.
PI: Alexander W. Sokolovsky, Assistant Professor of Behavioral and Social Sciences
Co-PI: Jasjit S. Ahluwalia, Professor of Behavioral and Social Sciences, Professor of Medicine, and Director, Population Sciences for the Brown Cancer Center
Humanities and Social Sciences
Informal Transit Networks in Emerging Cities
African cities will double in population by 2050, and will require thoughtful solutions to get around. In many emerging cities, transit is private: operated by many small bus companies, some so small they only own a single bus. This system is flexible, but can be disorganized and dangerous. In recent years, many cities have invested in formal public transit to replace private transit. But mass rapid transit is costly. And it may not be necessary: new technologies like dynamic routing may make it possible to increase the efficiency of decentralized transit, without the need for costly investment. This project will develop a new data partnership to study transport in Africa’s largest city. It will use that partnership to study how informal transit systems respond when the city of Lagos, Nigeria, introduces 820 new formal, government-owned and regulated buses across 50 routes. The study will assess how the introduction of this new travel option affects riders and operators, in collaboration with the Lagos Metropolitan Area Transport Authority (LAMATA).
PI: Daniel Bjorkegren, Assistant Professor of Economics
Unmasking COVID-19: Pacific Islanders, Health Equity, and Survival in New Zealand and the United States
“Unmasking COVID-19” examines the disproportionate effects of the coronavirus pandemic on Pacific Islander communities in New Zealand and the United States. While both countries have adopted different approaches to managing the pandemic at a national level, Pacific Islanders in both nations have been diagnosed with and suffered the impact of COVID-19 in numbers disproportionate to their representation within the overall population. Thus, a closer investigation of the historical and structural factors shaping Pacific Islanders' health outcomes, the pandemic’s role in exacerbating those factors, and local level organizations’ role in mitigating the impact of these circumstances is needed. Our team will conduct interviews with leaders and members of Pacific Islander serving organizations in New Zealand and the United States that have actively sought to provide much-needed community assistance during the pandemic. These interviews will then be supplemented by interviews with physicians and local government officials. Drawing on this data we will: (1) co-author and publish a series of Op-Ed pieces in New Zealand and U.S. news outlets on COVID-19’s disproportionate impact on Pacific Islander communities; (2) develop and publish a co-authored research paper on the importance of reconciling national and community-based narratives during the coronavirus pandemic; (3) build a website using the StoryMaps platform to showcase the virus’s impact on individuals’ everyday lives and highlighting the diverse array of community-based responses to managing the pandemic’s effects; and (4) apply for external grant funding to include additional nations/overseas territories across the Pacific region.
PI: Kevin Escudero, Assistant Professor of American Studies
Co-PIs: Keith Camacho, Associate Professor of Asian American Studies, University of California, Los Angeles; Maryann Nanette Anesi Heather, Senior Lecturer, School of Population Health, Faculty of Health and Medical Sciences, University of Auckland and General Practitioner, South Seas Healthcare
Disrupted Dreams: Understanding the Impact of Covid-19 on the Life Projects of First-Generation College Students and their Parents
This project makes use of the Pandemic Journaling Project (PJP) – an online journaling platform that Mason and Willen created and launched in May 2020 to chronicle and preserve first-hand experiences of the pandemic. We will examine the impact of the Covid-19 pandemic on the entwined life projects of first-generation college students and their parents. We ask: Has the Covid-19 pandemic impacted the content or trajectory of the life projects of first-generation college students and their parents, and if so, how? We will use a mixture of online journaling, semi-structured interviews, focus groups and the curation of an online photo exhibition to answer this question. Seed funds from Brown would allow Mason, Willen, Flores and Baines to build a long and lasting collaboration, would ensure the viability of the PJP platform through 2021, and would position our group well to procure extramural funds for this project. PJP currently has about 750 users and more than 6700 journal entries have already been submitted. By assisting our group in demonstrating that this platform can successfully be utilized to conduct virtual ethnographic research on a timely topic of importance during the pandemic, Brown can establish itself as a leader in virtual research methods in anthropology and education.
PI: Katherine Mason, Vartan Gregorian Assistant Professor of Anthropology
Co-PIs: Andrea Flores, Assistant Professor of Education; Sarah Willen, Associate Professor of Anthropology, University of Connecticut
Re-constructing Reza Abdoh's Father Was a Peculiar Man
Queer Iranian American director Reza Abdoh’s Father was a Peculiar Man is an important work of US avant garde theatre history. Based on Fyodor Dostoyevsky’s Brothers Karamazov, the play, combined aspects of the novel with other texts that explored the relationship between patriarchy, violence and the AIDS crisis. Father was staged in New York City’s meatpacking district—near sites of queer sex commerce and celebration in 1990. Unlike Abdoh’s other works, Father was never edited into a production video because it was a highly moveable site-specific performance which was nearly impossible to “capture” in a linear format. This project attempts to creatively reconstruct this performance through a multimodal digital archive of the performance including video footage, artist testimony, an annotated production “script,” critical essays and an urban spatial representation of the play. This project has two major contributions: 1) Providing scholars with access to a performance that radically shaped this history of avant-garde performance, and queer performance 2) modeling a new way of recreating performance works that are left out of traditional archives. A seed grant will fund the work of a research assistant (who has begun work as an UTRA recipient) and team of artists involved in the production to curate and organize the content to be made into the annotated reconstruction of the performance and to provide basic technical support for this project. This award will advance Brown's reputation for innovative arts scholarship in the digital humanities.
PI: Patricia Ybarra, Professor of Theatre Arts and Performance Studies
Humanities and Social Sciences
Petra Terraces Archaeological Project
The Petra Terraces Archaeological Project (PTAP) aims to study the long-term history of agricultural infrastructure in the hinterlands of the ancient city of Petra in southern Jordan. The project brings together an international team of archaeologists, anthropologists, geologists, and architects to study the construction, use, repair, and collapse of ancient terrace walls, dams, and related anthropogenic features that have enabled agriculture in a semi-arid environment over the last three thousand years. PTAP’s purpose is to produce a detailed, diachronic analysis of how people have shaped the local landscape by controlling—and at times also failing to control—flows of water and sediments along a single major watershed north of the city. The project builds on previous work by Brown archaeologists, both in the Petra city center, and more recently, in Petra’s outskirts. Specifically, it expands and refines the findings of an ambitious regional survey (based at Brown) that documented the ubiquity of anthropogenic modifications in the northern hinterlands of the city. PTAP will shed light on various matters of urgent importance in the contemporary Levant such as environmental inequality, human resilience and adaptability, and local responses to colonialism and imperialism, while also strengthening Brown’s ties to academic and non-academic communities in Jordan and neighboring regions.
PI: Felipe Rojas, Associate Professor of Archaeology and the Ancient World and Egyptology and Assyriology
Finding Social Narratives in Big Data
Decades of social science research has taught us that social discourse is governed by narratives, stories about how actors’ intentions and actions relate to outcomes. The narratives one buys into reflect one’s affiliations and how one makes sense of the social world. We are a team of cognitive scientists, applied mathematicians, and computer scientists. We propose to use cutting edge machine learning technology—OpenGPT-2, a deep learning algorithm partly developed at Brown—to discover the narratives that guide social discourse using big data from online sources. In the process, we hope to develop a general theory of narrative that can be computationally realized. Our plan is to examine text generated by OpenGPT-2 on three classes of topics: Topics showing significant polarization in the US (e.g., immigration); topics with less polarization, reflecting emerging consensus (e.g., gay marriage); and non-political topics such as video game strategies. We will analyze the text with the goal of developing a formal model of the narratives underlying discourse, apply that model to enhance understanding of what OpenGPT-2 is doing and to improve the theory and measurement of narratives in discourse, and increase the scalability of these methods to ease application to different timeframes and disparate cultures. The work is inherently interdisciplinary involving both computational and social sciences, with implications for machine learning and theories of narrative. It will cement Brown’s status as a hub for cutting edge research that applies computational methods informed by cognitive science to social issues.
PI: Steven Sloman, Professor of Cognitive, Linguistic and Psychological Sciences
Co-PIs: Bjorn Sandstede, Royce Family Professor of Teaching Excellence, Professor of Applied Mathematics, Director of the Data Science Initiative; Ellie Pavlick, Assistant Professor of Computer Science; Carsten Eickhoff, Assistant Professor of Medical Science, Assistant Professor of Computer Science
Key Personnel: Babak Hemmatian, Graduate Student, Cognitive, Linguistic and Psychological Sciences
Biological and Life Sciences
Investigating the neural basis of sequential control in obsessive compulsive disorder
Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder that affects ~2% of the population over their lifetime and is associated with impairments in behavioral flexibility and compulsive, ritualistic behaviors. Such behaviors can often be conceptualized as sequences that are stuck in a “loop” and have to be performed repeatedly and in a ritualized way, such as hand washing or lock checking. As shown by Dr. Desrochers, control over behavioral sequences is governed by an increase in activity (“ramp”) from the beginning to the end of the sequence in the frontal polar cortex (FP) of healthy adults. Sequence performance is disrupted with transcranial magnetic stimulation (TMS) to the FP. The FP is also known to show reduced recruitment in OCD during a variety of experimental paradigms. We hypothesize that patients with OCD may have a deficit in this ramping activity in the FP. Dr. Garnaat is a licensed clinical psychologist and expert in OCD who has recently been awarded a grant to study cognitive flexibility in OCD patients (and healthy age-matched controls) using fMRI and TMS, with the FP as a main target. We therefore propose to expand Dr. Desrochers’ research into a new field, research in clinical populations with OCD, in collaboration with Dr. Garnaat. The proposed project will capitalize on the patient recruitment, assessment, and experiments already scheduled with Dr. Garnaat’s funded project to add a component to scan OCD patients performing a sequential task. These studies will compliment both lines of research, and contribute to our fundamental understanding of the neural circuits underlying OCD.
PI: Theresa Desrochers, Rosenberg Family Assistant Professor of Brain Science, Assistant Professor of Psychiatry and Human Behavior
Co-PI: Sarah Garnaat, Assistant Professor of Psychiatry and Human Behavior (Research)
New biomarkers for neurodegenerative diseases
Neurodegenerative diseases represent a major threat to human health. We here propose to establish the experimental protocols and analyses pipelines for the discovery of new biomarkers for neurodegenerative diseases. Specifically, we will take advantage of access to the cerebral spinal fluid (CSF) of patients with normal pressure hydrocephalus, a neurodegenerative disease characterized by progressive cognitive and motor deficits. We will use state-of-the-art proteomics, metabolomics and next generation RNA sequencing technology to identify alterations in the expression of molecular signaling pathways that correlate with clinical signs of the disease. To this end, we will develop supervised and unsupervised machine learning algorithms to extensively mine the gene and metabolite expression data obtained from patient samples. We will specifically test the hypothesis that inflammation is a causative mechanism driving neurodegeneration. Our short-term goal is to identify new CSF biomarkers for normal pressure hydrocephalus, and to establish experimental and analysis pipelines that will allow us to extend our approach to target other neurodegenerative diseases including Alzheimer’s Disease. Our interdisciplinary project is timely and highly innovative, bringing together world-class expertise in neurosurgery, molecular neurobiology, and data science. Preliminary results obtained with OVPR support will allow us to attract long-term financial support through federal grants, private foundations, and industry partnerships.
PI: Alexander Fleischmann, Provost's Associate Professor of Brain Science
Co-PIs: Petra Klinge, Professor of Neurosurgery, Director Pediatric Neurosurgery Division, Director of the Research Center and Clinic for Cerebrospinal Fluid Disorders; Thomas Serre, Associate Professor of Cognitive, Linguistic and Psychological Sciences (CLPS), Director of the Center for Computation and Visualization
Neural Metabolomics and infantile epilepsy associated with mutations in SLC13A5
SLC13A5 deficiency is a newly diagnosed form of genetic epilepsy and developmental delay with seizures beginning within the first days of life. In these patients, homozygous mutations in the SLC13A5 gene, which encodes a plasma membrane citrate transporter result in a severe, early onset multi-focal epilepsy, in addition to cognitive and behavioral symptoms. Progress in finding treatments for this condition has been hampered by the lack of appropriate models to study the brain phenotype. We have already developed a novel model with the human SLC13A5 gene transgene inserted into a mouse with a deletion of the native murine Slc13a5. This mouse expresses only the fully human SLC13A5 in the central nervous system. Furthermore, we have created a knock-in of the human SLC13A5 with pathogenic mutations in Drosophilia. The studies proposed here are for the purpose of creating the full panel of model systems with pathogenic mutations and to obtain preliminary data needed for the submission of a multi-investigator grant to the NIH in order to address key questions: 1) what is the normal function of SLC13A5 in brain physiology 2) how do pathogenic mutations in SLC13A5 result in neural dysfunction and 3) what are the genetic modifiers of SLC13A5 which affect disease expression. This will begin to address our underlying hypothesis that epilepsy associated with SLC13A5 is related to specific neuronal metabolic requirements, which impact neuro-transmitter pools. The identification of the metabolic and neurotransmitter changes may lead to new treatments for epilepsy and also cognitive/ behavioral symptoms associated with SLC13A5.
PI: Judy Liu, Sidney A. Fox and Dorothea Doctors Fox Associate Professor of Ophthalmology and Visual Science, Associate Professor of Neurology, Associate Professor of Molecular Biology, Cell Biology and Biochemistry
Co-PI: Stephen Helfand, Professor of Biology, Vice Chair of Neurology
Dissociating Neurocomputational Mechanisms Underlying Positive and Negative Motivations for Cognitive Effort
When deciding how much effort to invest in a given task, individuals weigh both positive outcomes that could accrue (e.g., praise) as well as negative outcomes such efforts could avoid (e.g., admonishment). However, little is known about the neural and computational mechanisms by which different incentives determine how much and how long we invest effort into cognitively demanding tasks, including whether different substrates exist for different strategies for responding to negative incentives (e.g., working harder vs. more cautiously). Moreover, while both incentives contribute to one's decision to invest effort, a person's relative sensitivity to negative versus positive incentives can significantly impact their health and wellbeing, leading to chronic stress and anxiety. This proposal aims to identify neural substrates underlying cognitive effort allocation in the face of these different incentive types, and measure how differences in sensitivity to these incentives influence a given person's motivation to invest effort in their daily tasks as well as their susceptibility to negative health outcomes. We will leverage a computational model our lab has developed to predict variability in effort investment, combining this model with measures of behavior and neural activity taken while participants perform a novel task. This work will bridge research in neuroscience, economics, psychiatry, and public health, and advance Brown’s position across those fields. Receiving an OVPR Research Seed Fund Award to carry out this foundational research will position us to apply for external funding to make further inroads into what motivates people to exert the effort necessary to achieve their goals.
PI: Amitai Shenhav, Assistant Professor of Cognitive, Linguistic and Psychological Sciences
Co-PI: Debbie Yee, Postdoctoral Research Associate, Cognitive, Linguistic and Psychological Sciences
Biological, Life, and Physical Sciences
Smarter AI: Designing Autonomous Systems that Optimize Hardware, Software and Cognitive Components Together
Deep learning (e.g., convolutional neural networks (CNNs)) has gained a lot of attention in the past few years, especially for object identification and classification problems. Despite their strengths, CNNs have several shortcomings, such as their opacity to understand how they make decisions, fragility for generalizing beyond overfit training examples, and inability to recover from bad decisions. These weaknesses play to the strengths of techniques in artificial intelligence (AI) based on generative probabilistic inference, techniques that are inherently explainable, general, and resilient by distribution of many hypotheses representing possible decisions. Unfortunately, probabilistic inference, in contrast to CNNs, is often computationally intractable with complexity that grows exponentially with the number of variables. Combined discriminative-generative algorithms have been proposed as a promising avenue for robust perception by balancing computational complexity with explainability and reasoning, but still may not provide for real-time response, even after careful optimization. Instead, we propose bringing humans back into the loop to provide essential functionality to guide decisions, planning, and management of an AI-enhanced system. In particular, the models that have proven useful for understanding human agency are Causal Bayes Nets. This project seeks to explore how humans and intelligent computers can collaborate effectively by integrating technical functions (i.e., discriminative-generative decision making) with human cognitive processes. A driving theme of this exploration will be complexity (and energy) optimization. Applying more effort and thereby computational and cognitive assistance in a hybrid fashion, and only as needed, will minimize energy consumption, improve response time, and be more likely to optimize users’ needs.
PI: R. Iris Bahar, Professor of Computer Science, Professor of Engineering
Co-PI: Steven Sloman, Professor of Cognitive, Linguistic and Psychological Sciences
Key Personnel: Odest Chadwicke Jenkins, Associate Professor of Computer Science, University of Michigan, Ann Arbor
Novel analogs of trehalose for treatment of preeclampsia, a devastating pregnancy complication
Trehalose has been found to be an effective treatment for preeclampsia, a potentially life-threatening condition affecting some pregnant women. Unfortunately, administration of trehalose can result in additional complications from undesired bacterial growth and infection from microbes that metabolize trehalose. We propose to prepare analogs of trehalose that retain efficacy in the treatment of preeclampsia but cannot be utilized by bacteria. The prepared analogs will be evaluated using a variety of models for their effectiveness in treating preeclampsia while not serving to promote bacterial growth. The project team of Basu and Sharma provide expertise in carbohydrate synthesis and preeclampsia biology respectively.
PI: Amit Basu, Associate Professor of Chemistry
Co-PI: Surendra Sharma, Professor of Pediatrics (Research), Professor of Pathology and Laboratory Medicine (Research)
Computational Modeling of Blood Flow to Understand Microvascular Dysfunction in Alzheimer's Disease
Alzheimer’s disease (AD), a progressive neurodegenerative disorder affecting millions of people worldwide, and related dementia are becoming the biggest epidemic in medical history. However, AD is a heterogeneous and multifactorial disease, making it challenging to fully understand how the multiple etiologies and age-related prodromal processes in AD contribute to its pathophysiology. Among other factors, deficits in cerebral microvascular structures and functions are recently considered to play a key role in the onset and development of AD. But, it is still unclear whether they are a causal factor for AD pathogenesis or an early consequence of multifactorial conditions that lead to AD at a later stage, despite its importance for early diagnosis and as a therapeutic target. To address this knowledge gap, we performed a longitudinal imaging experiment of tracking progressive microvascular alterations in AD mice for almost their lifespan. Although these data provide us with unprecedently rich information about various cerebral microvascular deficits and cognitive impairment, they were insufficient to determine the cause-effect relationships. Here, in this Seed project we will develop a computational methodology to investigate the mechanistic question. First, we will improve our computational model of microvascular flow and functional hyperemia (Aim 1), and then combine the model with the experimental data for the mechanistic study (Aim 2). The computational model will enable us to essentially “turn on” and “turn off” each microvascular deficit (e.g., thinner vessels, tortuous capillaries, hypoperfusion) and test its effect on oxygen delivery to neurons, which is difficult and sometimes impossible to achieve experimentally.
PI: Jongwhan Lee, Assistant Professor of Engineering
A new direction in building quantum computers: 2D material "lego"
Reducing a material to the atomic 2-dimensional limit has been shown to have profound effects on its properties. Since the successful exfoliation of graphene from bulk graphite , a large family of layered van der Waals materials have been thinned down to a single atomic layer, forming a new material platform covering a wide range of physical properties. The van der Waals assembly technique allows any 2D material to be re-assembled into a designer structure, which has recently led to a flurry of discoveries establishing 2D material heterostructure as a new paradigm for discovering novel quantum phenomena and advancing our understanding of quantum science. Here, we propose a new direction to study an entangled quantum phenomenon called Majorana mode, which is at the heart of topological quantum computation. The PIs plan to develop the capability of thermal transport measurement on materials that are one-atomic layer thin. Measurements of quantized thermal conductance in these materials will offer direct and unambiguous identification of Majorana modes. This effort will build on the established expertise of the PI and co-PI. Prof. Li has developed the necessary techniques of working with 2D materials and performing quantum transport measurements, Prof. Plumb is a leading expert in bulk material growth and neutron scattering, and Prof. Feldman has done pioneering research on Majorana modes in the 2D limit. The proposed effort will establish Brown University as a center for studying and engineering future 2D magnetic material and nano-scale quantum technology.
PI: Jia (Leo) Li, Assistant Professor of Physics
Co-PIs: Kemp Plumb, Assistant Professor of Physics; Dmitri Feldman, Professor of Physics
Search for Topological Waves in Magnetized Gaseous Plasmas
Funds are requested to purchase electronic equipment and cover travel expenses to UCLA's Basic Plasma Science Facility (BaPSF) to make a first observation of a plasma wave of topological origin using the Large Plasma Device (LAPD). The search was inspired by my 2017 Science paper ""Topological Origin of Geophysical Waves"" that reported the surprising discovery that Kelvin and Yanai waves have a topological origin analogous to edge modes in the quantum Hall effect. My collaborators and I have now theoretically predicted, and simulated, other waves of topological origin in a magnetized plasma. We used a realistic model of the LAPD plasma, and the Director of BaPSF (Troy Carter) has granted us time on the LAPD to conduct experiments provided that we can supply the necessary microwave amplifier to drive the waves. If the existence of the waves is confirmed by experiment, it would represent a breakthrough in plasma physics likely leading to both publication in prestigious journals and external funding.
PI: Brad Marston, Professor of Physics
Key personnel: Jeffrey Parker, Research Scientist, Lawrence Livermore National Laboratory; Steven Tobias, Professor of Applied Mathematics, University of Leeds, UK; Ziyan (Zoe) Zhu, Graduate Student, Department of Physics, Harvard University
Confronting the Data Deluge using Quantum Machine Learning
One common application of data science across scientific domains is extracting signals from increasingly large data sets. Recent advances in deep learning and artificial intelligence have become a practical necessity for such applications. Given the size of the datasets and the ever growing needs for CPUs for effective training of deep learning algorithms, quantum computing is an attractive solution. Even though there are remaining challenges to make quantum computing devices widely usable, it is important to understand and explore what this new technology and applications of quantum computing algorithms could bring to our fields. We propose to use quantum simulators to perform sensitivity studies for extracting rare signals of new physics in the environment proposed for future particle colliders and free electron lasers. The proposed interdisciplinary work has important implications beyond the disciplines involved as it will develop the technology of quantum machine learning. As quantum computers become available they will allow us to meet computational challenges in many fields and solve scientific questions that are out of reach with current technologies. This seed project will complement and strengthen the core group of faculty members in Physics and Chemistry who explore quantum information science.
PI: Meenakshi Narain, Professor of Physics
Co-PIs: Brenda Rubenstein, Assistant Professor of Chemistry; Peter Weber, Professor of Chemistry
Cosmic History from Mapping the Universe with Neutral Hydrogen
Measuring the intensity of 21 cm emission from neutral hydrogen gas is a novel technique that enables mapping large volumes of the universe in three dimensions. The Tianlai Pathfinder has been carrying out a North Celestial Cap Survey (NCCS). The Tianlai Pathfinder is unique among 21 cm instruments in being able to point and integrate continuously on a limited patch of sky for extended periods. With seed funding Brown could contribute to analyzing this rich data set and produce initial results which will strengthen subsequent proposals. One of the ultimate goals of this research is to measure baryon acoustic oscillations over cosmic time to help understand dark energy, which is currently not understood. This research will also, for example, shed light on the mysterious fast radio bursts (FRBs), detect radio counterparts of gravitational events from sources such as merging neutron stars and lead to a better understanding of galaxy formation. The Tianlai Pathfinder will demonstrate the feasibility of using wide field of view radio interferometers to map the density of neutral hydrogen in the universe after the Epoch of Reionization (EoR). Such radio interferometers are relatively new, and the necessary techniques are still being developed. The Tianlai Pathfinder is also unique in that it consists of two co-located interferometers utilizing different types of antennae (cylinders and dishes), which provides an important opportunity to compare the ultimate performance of these two types of telescopes as the next generation of more sensitive instruments is planned.
PI: Gregory Tucker, Professor of Physics
Is greenspace associated with mental and physical health among pregnant women? A geo-ethnographic exploration
Exposure to greenspace, broadly defined as various forms of vegetation, has been shown to confer various health benefits. Specifically, reducing the likelihood of adverse birth outcomes, reducing the mental health impact of stressful life events, decreasing symptoms associated with behavioral problems, as well as reducing the risk of the onset of obesity. The evidence base of the positive impact of greenspace on health has proliferated to such an extent that in 2015, the United Nations adopted the exposure to greenspace as a sustainable development goal, with target 11.7 stating "By 2030, provide universal access to safe, inclusive and accessible, green and public spaces, particularly for women and children, older persons, and persons with disabilities." With regard to the association between greenspace and birth outcomes, however, the findings are equivocal. The purpose of this multidisciplinary collaboration across public health, medicine, and geography is to attempt to reconcile conflicting findings on the association between greenspace exposure and birth outcomes. By examining the relative contributions of varying measures of green space exposure hypothesized to be associated with mental and physical health during pregnancy, we hope to develop the types of assessments that capture the relevant environmental features that will permit a better understanding of the mechanisms that underpin associations between greenspace exposure and birth outcomes.
PI: Diana Grigsby-Toussaint, Associate Professor of Behavioral and Social Sciences
Co-PIs: Patrick Vivier, Professor of Health Services, Policy and Practice, Professor of Pediatrics, Professor of Emergency Medicine; Kevin Mwenda, Assistant Professor of Population Studies, Associate Director, Spatial Structures in the Social Sciences (S4)
The effect of a driver's license suspension on access to health care
Every year approximately 3.6 million Americans miss or delay health care due to transportation barriers. Though lacking access to a vehicle is the most commonly reported transportation barrier to care, 43 states currently have policies to suspend driver’s licenses as a means of compelling compliance with laws and regulations unrelated to driving (e.g., failure to pay a court fee or appear in court). Approximately 80% of all suspensions are for a non-driving-related offense, and the impact of these suspensions falls primarily on low-income and racial/ethnic minority drivers. Supporters of suspensions view them as one of a limited set of tools for compelling compliance with state regulations. However, little is known about the population of suspended drivers, or the unintended consequences of a suspension for accessing health care. We propose to close this gap using a unique dataset of linked driver’s licensing histories with Medicare and Medicaid claims to provide the first individual level descriptions of this population and how it has changed over time. In the last two years, six states have passed legislation ending non-driving-related license suspensions and several more are considering doing the same. The findings from our proposed work will provide policy makers with the essential information on suspended drivers necessary for developing informed and effective suspension policies and will establish the empirical foundation required for extending our work to estimate the causal effect of a suspension on access to health care, health care utilization and ultimately health outcomes.
PI: Nina Joyce, Assistant Professor of Epidemiology
Co-PI: Andrew Zullo, Assistant Professor of Health Services, Policy and Practice, Assistant Professor of Epidemiology
Co-Is: Jasjit Singh Ahluwalia, Professor of Behavioral and Social Sciences, Professor of Medicine; Allison E. Curry, PhD, MPH, Assistant Professor of Pediatrics, Division of Emergency Medicine, University of Pennsylvania Perelman School of Medicine, and Senior Scientist and Director of Epidemiology and Biostatistics, Center for Injury Research and Prevention, Children’s Hospital of Philadelphia; Melissa Pfeiffer, MPH, Senior Biostatistician, Center for Injury Research and Prevention, Children’s Hospital of Philadelphia
Improving maternal and child health starting in pregnancy: examining cardio-metabolic risk among women living with and without HIV and their children in South Africa
Each year in sub-Saharan Africa, over 1 million children are born exposed to HIV-infection in utero, but uninfected (HEU). Compared to HIV-unexposed (HU) children, HEU face a range of health consequences including metabolic abnormalities, such as hypertension, dyslipidemia, and impaired glucose function. To date our understanding of factors that affect metabolic health of women living with HIV and their children has been hampered by the vastly different social environments and health status between those living with and without HIV. These differences may lead to important variations in maternal biomedical and psychosocial factors during pregnancy, such as maternal substance use, food security, body mass index, gestational weight gain, which may influence long-term metabolic health for both women and children but have not been explored in HIV-infected populations. This proposal brings together the unique disciplinary perspectives of a psychologist and an epidemiologist to examine how maternal factors during pregnancy influence metabolic outcomes in women and children and to design an intervention to mitigate these factors to be evaluated through subsequent external funding. We propose to leverage the Drakenstein Child Health study, an established cohort of mother-child pairs in South Africa with rich psychosocial and biomedical data. OVPR Seed Funds will be used to examine markers of metabolic function during pregnancy and prospectively evaluate metabolic outcomes in women and children at 5-8 years postpartum. We expect this pilot award to result in a R01 application focused on testing an intervention to improve cardio-metabolic outcomes in women with and without HIV and their children.
Co-PIs: Angela Bengtson, Assistant Professor of Epidemiology; Jennifer Pellowski, Assistant Professor of Behavioral and Social Sciences
Co-I: Stephen McGarvey, Professor of Epidemiology, Director of International Health Institute
Key Personnel: Heather Zar, Professor & Head of the Department of Paediatrics and Child Health, University of Cape Town, South Africa; Dan Stein, Professor & Head of the Department of Psychiatry and Mental Health, University of Cape Town, South Africa
“Education, Not Deportation": Immigrant Law and Medical Students' Experiences Across Legal Status
As scholars and policy makers alike have noted, currently there is urgent need for increased numbers of culturally competent professionals in the legal and medical fields. This is particularly important given the decisive role medical and legal services play in the everyday lives of community members. Also, given recent developments in federal immigration policies, increased numbers of undocumented students have been able to enroll in professional degree programs. Social science research has largely examined undocumented students’ experiences along the educational pipeline separate from that of their U.S. citizen, legal permanent resident peers. This project seeks to bridge this gap by examining the experiences of immigrant students -- documented and undocumented -- alongside one another to focus on the role legal status plays in shaping educational access and post-graduate opportunities. Employing the use of a mixed methods approach consisting of an online survey of immigrant law and medical degree students and in-depth interviews, this project aims to create a database that can be of use to future scholars interested in issues of immigration, educational equity, and the legal and healthcare professions.
PI: Kevin Escudero, Assistant Professor of American Studies
Co-PIs: Tina M. Park, Ph.D. candidate in Sociology; Rachel Freeman, Ph.D. candidate in Education, UCLA; Vania Pereira, M.A. candidate in American Studies; Marco Antonio Flores, M.A. candidate in Art History, Williams College
A Collaborative Research Initiative on Children’s Alternative Care
UNICEF estimates that there are approximately 153 million orphaned and abandoned children worldwide, most in low- and middle-income countries. While roughly 2.7 million children reside in formal institutional care such as orphanages (Petrowski et al 2017), millions more live in “alternative care,” which includes care with extended kin, foster care, and family-like care. Efforts to support children in need of alternative care are complicated by a lack of rigorous academic research that can be used to inform best practices and program design. Our project on children’s alternative care will bring together Brown faculty in anthropology, sociology, public health who have expertise in studying children’s alternative care and child and family health and well-being. Our goal is to develop a large-scale, multi-disciplinary project on alternative care in low- and middle-income countries. In partnership with global and local care providers, we propose to study how different experiences of alternative care affect child health and resilience, shape conceptions of identity for children and their caregivers, and explore how public health, policy, community and family contexts are related to caregiver and child experiences and well-being. In so doing, we seek to produce results that expand scientific understanding of alternative care, and inform efforts to advocate for and provide care for children in need around the world.
PIs: Jessaca Leinaweaver, Professor of Anthropology, and Susan Short, Professor of Sociology
Co-PI: Caroline Kuo, Associate Professor (Research) of Behavioral and Social Sciences
Political Knowledge and Citizenship in Developing Country Democracies
James Madison famously wrote that a “popular government, without popular information or the means of acquiring it, is but a prologue to a farce or a tragedy.” In recent years, citizen political knowledge and the challenges of misinformation have received substantial attention in the United States and other wealthy democracies. Of note, however, is the fact that a majority of citizens living under democratic governments today live in lower and middle-income countries. In these contexts, citizen knowledge is crucial not only for making voting decisions, but for gaining access to basic rights and entitlements. There is surprisingly little research on citizen political knowledge in lower and middle income democracies, how that knowledge affects voting and other political behaviors, and the conditions under which citizens invest greater time and effort in acquiring relevant political knowledge. This is part of a larger project in which we will carry out large citizen surveys in a number of lower and middle-income democracies, including Brazil and Indonesia (the latter funded by Brown's Seed grant). These surveys will explore how best to measure political knowledge, the links between knowledge and the ability to exercise the full rights of citizenship, as well as the conditions that lead citizens to acquire political knowledge from reputable sources. Another outcome of this project will be the development of a new battery of political knowledge questions that can be used in single-country and cross-national surveys in democracies across the developing world.
PI: Rebecca Weitz-Shapiro, Associate Professor of Political Science
Co-PI: Matthew Winters, Associate Professor of Political Science, University of Illinois at Urbana-Champaign
Biological and Life Sciences
The neural architecture of political polarization: How polarized perception arises and how to overcome it
Humanity’s greatest triumphs require extensive cooperation between people with opposing viewpoints, but this principle is under threat from political polarization. At the heart of polarization lies ‘polarized perception’: our political beliefs fundamentally change the way we perceive the world. This can, in turn, intensify our beliefs and undermine cooperation. To design effective interventions against polarization, it is crucial to understand which psychological mechanisms drive polarized perception. Despite the urgency of this problem, it remains largely unknown which psychological mechanisms contribute to polarization, impeding finding successful interventions. The aims of this proposal are to establish a new theoretical and methodological model for studying polarization, and to use cutting-edge methods in neuroscience, including inter-subject neural synchrony, to identify which components of this model give rise to political polarization. Crucially, this approach will identify which elements of political communication (e.g. emotional language) elicit the greatest polarized perception, which can yield promising new avenues for tackling the increasing polarization we see unfolding in society. This project will thus initiate a highly innovative research line aimed at understanding polarization from a neuropsychological perspective, while also providing practical solutions. By building bridges between traditionally distant fields and bringing in knowledge on state-of-the-art methodology, this research will advance the position of Brown University in psychology, political science, and neuroscience. An OVPR Research Seed Fund award will allow us to demonstrate how neuroscience can revolutionize polarization research, forge collaborations with leading experts around the world, and secure the external funding needed to discover how we overcome political polarization.
PI: Oriel FeldmanHall, Assistant Professor of Cognitive, Linguistic & Psychological Sciences
Co-PI: Jeroen Van Baar, Postdoctoral Research Associate in Cognitive, Linguistic & Psychological Sciences
Progressive neurodegeneration in mouse models of amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive degradation of neuromuscular connectivity, leading to widespread paralysis and ultimately death of affected individuals. Effective therapeutic intervention in ALS presents an unmet medical need, and accurate animal models of the disease are required as a proving ground for treatment approaches. We have recently begun to characterize a novel genetic knock-in model of ALS in mice, and our preliminary findings provide strong evidence for muscle denervation and motor deficits in this mouse line. We hypothesize that these mice are an accurate disease model that recapitulates the progressive neurodegenerative features, focal spread, and sex-specific differences of ALS. We propose to further characterize neuromuscular deficits in this mouse line, using both anatomical and behavioral criteria to follow symptomatic progression in different muscle groups of both male and female mice over time. Insights gained from these initial studies will position us to compare multiple ALS models, discover common disease mechanisms, and provide a reference framework for assessing the effectiveness of various manipulations that might delay or prevent symptomatic progression. Thus, our work is an important step towards the development of therapeutic strategies for ALS.
PI: Alexander Jaworski, June G. Zimmerman Assistant Professor of Brain Science, Assistant Professor of Neuroscience
Key Personnel: Diane Lipscombe, Thomas J. Watson, Sr. Professor of Science, Professor of Neuroscience; Justin Fallon, Professor of Medical Science, Professor of Psychiatry and Human Behavior; Eric Morrow, Mencoff Family Associate Professor of Biology, Associate Professor of Neuroscience, Associate Professor of Psychiatry and Human Behavior
Drug discovery for falciparum malaria
The overall aim of this application is to discover novel therapeutics for Plasmodium falciparum malaria. P. falciparum is a leading cause of morbidity and mortality in developing countries, infecting hundreds of millions of individuals and killing over one million children each year. The spread of parasites resistant to the artemisinin family of compounds threatens recent progress achieved by antimalarial campaigns and underscores the urgent need to identify new anti-malarial drugs. In previous work, we discovered PfGARP, a previously unrecognized parasite protein found on the exofacial surface of parasite-infected erythrocytes. Antibodies to PfGARP inhibit parasite growth in vitro by 99% compared to controls in the absence of any immune effector molecules (complement) or cells- thus the remarkable anti-parasite effect of anti-PfGARP results from antibody binding alone. The Scientific Premise of this application is that PfGARP is a high value, druggable target based on: 1) its surface expression on infected RBCs, 2) the absence of any significant amino acid homology with human host proteins, and 3) the ability of antibody binding to PfGARP to kill essentially all exposed parasites within 12 hours.In this application, we will screen a large drug library (30 million compounds) to identify drugs that bind to PfGARP and mimic the activity of anti-PfGARP antibodies, resulting in rapid parasite death.
PI: Jonathan Kurtis Stanley M. Aronson Professor of Pathology and Laboratory Medicine, Chair of Pathology and Laboratory Medicine, Professor of Pathology and Laboratory Medicine
Redox-Mediated Control of Protein Structure as a Potential Therapy for Inflammation
Macrophage migration inhibitory factor (MIF) is critical to the pathophysiology of inflammation and MIF inhibition or its deficiency in MIF-/- mice is strongly correlated with a reduction in respiratory disease symptoms. MIF promotes pro-inflammatory signaling through interactions with proteins involved in cellular redox regulation and its structure is believed to be sensitive to changes in cellular redox conditions. The potential to leverage this sensitivity to design effective MIF inhibitors will be enhanced by a detailed understanding of its redox-dependent properties, which have not been characterized. Such inhibitors have promising therapeutic value for treatment of inflammatory diseases, but these efforts are stalled by the lack of structural and dynamical information about the redox-dependent interactions of MIF with partner proteins, receptors and small molecules. Our preliminary data show that the MIF structure and conformational motions are altered by solution redox properties. I hypothesize that MIF modifies its structure in response to local redox potentials and that this conformational flexibility allows MIF to toggle its interactions with pro-inflammatory proteins, modulating downstream biological responses. This hypothesis will be tested by investigating the redox-dependent structure and conformational dynamics of MIF as well as its structure in complex with its CD74 receptor and redox proteins thioredoxin and ribosomal protein S19. The redox-dependence of drug-like ligand interaction with MIF will be determined to advance a novel approach toward selective MIF inhibition that will add to a strong track record of quality investigations into inflammatory/respiratory pathologies at Brown and may ultimately aid in the treatment of inflammatory diseases.
PI: George Lisi, Assistant Professor of Molecular Biology, Cell Biology & Biochemistry
Collaborator: Elias Lolis, Professor of Pharmacology, Yale School of Medicine
Structural Basis of Viral Attack on Innate Immunity
Promyelocytic Leukemia Nuclear Bodies (PML-NBs) are dynamic sub-nuclear organelles formed by protein PML and Sp100, with important contributions from the Small Ubiquitin-like MOdifier (SUMO) and numerous different partner proteins. Traditionally these have been studied in association with the acute promyelocytic leukemia, and are known to indirectly regulate diverse cellular processes like transcription, apoptosis, DNA replication, and epigenetic silencing. PML-NBs are also known to regulate the innate immune signaling pathways and have emerged as integral components of the host antiviral response. Recent studies show viruses have evolved mechanisms to disarm PML-NBs suggesting new functional roles played by them. Despite the high functional significance, we lack an understanding of interactions between PML-NB constituents and viral proteins. We show that JC and BK human polyomavirus interact differently with PML-NBs. This proposal is an attempt to bridge enigmatic knowledge gap by applying powerful NMR spectroscopy to elucidate the structural basis for PML-NB disruption by BKPyV.
PI: Mandar Naik, Assistant Professor of Molecular Pharmacology, Physiology and Biotechnology (Research)
Collaborator: Walter Atwood, Professor of Medical Science
The function of the extraocular Opsin 3 receptor in the brain
Visual phototransduction has received much attention over the past decades, while nonvisual phototransduction has been slower to gain interest despite sustaining equally important functions: from entraining circadian rhythms, to facilitating photorelaxation of blood vessels. The first mammalian extraocular opsins was identified twenty years ago in the hypothalamus and aptly named encephalopsin or opsin 3 (OPN3). Although we have recently discovered a function for OPN3 in the regulation of skin pigmentation, its function in the brain remains unknown. The goal of the proposed experiments is to understand the signaling mechanisms of OPN3 in the mammalian hypothalamus. Based on our preliminary data, the central hypothesis of this proposal is that OPN3 physically and functionally regulates melanocortin 3 receptor (MC3R) in the hypothalamus to negatively mediate energy balance. We will first investigate the cellular co-localization of OPN3 and MC3R in the hypothalamus using a novel OPN3-mCherry mouse that we recently generated, then test the functional interaction of the two receptors by measuring the receptor-mediated changes in cellular cAMP. These studies will uncover a novel functional role of mammalian OPN3 in the brain and will broaden our understanding of nonvisual phototransduction
PI: Elena Oancea, Associate Professor of Medical Science
Neural mechanisms of object recognition by hand and eye
The connection between eye and hand, or vision and touch, has puzzled philosophers, psychologists, and neuroscientists for hundreds of years. In the past few decades, considerable progress has been made in understanding mechanisms of visual recognition. Indeed, for primates, perceptual experience is very much dominated by vision and a large proportion of the brain is dedicated to visual processing. At the same time, however, knowing how we recognize objects by vision should not be mistaken for understanding how we know what objects are. This project will explore how we recognize objects by vision and by touch, and attempt to uncover the neural circuits by which this information is shared through the concerted activity of neurons in the brain. Understanding how the brain merges multiple sources of information into stable and meaningful representations of objects is of significant interest in that it can provide clues as to how these same circuits may result in dissociations between the senses in psychiatric disease.
PI: David Sheinberg, Professor of Neuroscience
Collaborator: Ryan Miller, Postdoctoral Fellow in Neuroscience
Structure and mechanics of the bat shoulder: Testing a new model for human rotator cuff disorders
To date, mice have served as the primary animal model for disorders of the human shoulder. However, mice differ from humans in fundamental and critical ways that limit this approach: during locomotion, impact loads apply compression/bending to the forelimb; mice experience relatively few loading cycles over their short lives; and mouse shoulder anatomy and patterns of motion differ greatly from those of humans. In contrast, bats are long-lived (typically 15 to 35 years), and their natural flight patterns entail a very large number of locomotor cycles (over 1,200,000 over 15 years). Anatomy of the bat shoulder skeleton, muscles, and tendons resembles that of humans remarkably closely, and shoulder motions used by bats during flight appear to closely match those of humans during high stress, injury-causing activities (throwing, swimming, racquet power strokes, overhead hammering). Moreover, the structures of the human-like bat rotator cuff appear to withstand mechanical demands that are extreme, in magnitude and number of repetitions, without the wear or damage that frequently result from occupational and athletic activities in humans. To determine feasibility of use of our laboratory bat colonies as a model for ongoing study, and specifically to develop collaborative proposals to NSF and NIH (with G. Genin, Washington University and S. Thomopolous, Columbia University), we propose to carry out two foundational analyses. We aim to demonstrate achievability of 1) accurate capture of 3D shoulder kinematics during controlled flight (wind tunnel and obstacle course) and swimming with XROMM, and 2) direct measurement of shoulder muscle activity patterns.
PI: Sharon Swartz, Professor of Biology, Professor of Engineering
BMP4 signaling in brain development and epilepsy
Epilepsy, often a consequence of abnormal neurological development, is a major co-morbidity of intellectual disability. Disruptions in brain development result in abnormal circuits that underlie functional neuronal deficits and alterations in homeostasis causing seizures. BMP4 is expressed in areas of the developing ventral forebrain that give rise to interneuron populations implicated in epilepsy. Studying the role of critical developmental signals, such as BMP4, that also appear to be important in epilepsy, has been hindered by the lack of good models, since the complete loss of gene function results in lethality early in development. We have generated mouse models that are partial loss of function for BMP4 signaling. These BMP4 mutant mice display severe epilepsy as adults with evidence of a change in the size of the cortex at 2 months. At that age, we observe the onset of epileptiform discharges. By late adulthood, we see an increase in cortical thickness in the mutant brains vs control. We propose that loss of fine-tuned BMP signaling causes neuronal and glial defects leading to epilepsy. We will test this hypothesis: Aim 1: Determine effect of dysregulated BMP4 signaling on cortical activity. Using video EEG, we will test our hypothesis that dysregulation of BMP signaling leads to progressive abnormal circuit dysfunction and epilepsy. Aim 2: Determine effect of compromised BMP4 signaling on brain structures implicated in epilepsy. We will test our hypothesis that abnormal BMP4 signaling causes structural changes underlying epilepsy, including changes in neural architecture and possible alterations in glial structure and function.
PI: Kristi Wharton, Professor of Biology
Co-PI: Judy Liu, Sidney A. Fox and Dorothea Doctors Fox Professor of Ophthalmology and Visual Science, Assistant Professor of Neurology, and Assistant Professor of Molecular Biology, Cell Biology & Biochemistry
Key Personnel: Allyson Sherman-Roe, Research Assistant in Molecular Biology, Cell Biology & Biochemistry
A novel gene therapy targeting cardiac fibroblast electrical remodeling to reduce fatal arrhythmias after heart attack
When an athlete suddenly drops to the ground and dies during competition, the cause is often “sudden cardiac death,” a medical term that means there was a severe problem with the electrical activity of the heart that caused it to stop beating. As we age, we all have an increased likelihood of developing heart disease, like having a heart attack or developing atrial fibrillation. Many of these heart conditions have interrupted electrical activity, called arrhythmias, yet current medical care for arrhythmia is technically challenging and often carries great risks, including worsening the problem. We aim to develop new, targeted gene therapies for arrhythmia by specifically instructing the fibroblasts of the heart to help manage the electrical patterns. These cells are very active and change their behavior as we age and particularly after a heart attack, becoming more agitated and excitable. Our research aims to calm down the electrical activity of fibroblasts and reduce fatal arrhythmias. To do this, we formed a multi-disciplinary team of experts in cardiac arrhythmia mechanisms, tissue engineering, and gene therapy. This project is expected to launch a new research enterprise at Brown that will lead the field in developing an understanding of fibroblast-driven arrhythmia mechanisms and advancing novel therapeutic strategies to treat arrhythmia and lessen the risks for sudden cardiac death.
PI: Kareen Coulombe, Assistant Professor of Engineering, Assistant Professor of Molecular Pharmacology, Physiology and Biotechnology
Co-PI: Bum-Rak Choi, Associate Professor of Medicine (Research)
Collaborators: Peng Zhang, Assistant Professor of Medicine; Ulrike Mende, Professor of Medicine
Key Personnel: Collin Polucha, Research Technician, Engineering; Tae Yun Kim, Postdoctoral Fellow, Medicine; Peter Bronk, Research Scientist, Medicine; Karim Roder, Assistant Professor of Medicine (Research)
Probing the role of mechanical forces in tissue assembly using in situ force sensors
The forces cells exert, and have exerted on them in return, play a critical role in early development, wound healing, and disease. However, these forces are not easily investigated, nor have they been quantified within 3D, cell-dense tissues. This information is critical for understanding cellular interactions necessary for tissue assembly and repair. The proposed project will investigate the role of intercellular forces in cell-dense structures. To accomplish this, we will quantify cell traction forces in 3D constructs by embedding discrete, hyper-compliant microparticles (HCMPs) alongside living cells and monitoring the resultant deformations. Existing approaches for quantifying traction forces require measuring the displacement of fiducial markers in bulk, deformable materials. That approach is not compatible for studying cell-only neotissues that serve as models of native tissue building. Instead, we will embed a small number of HCMPs of defined size (25 µm) and elastic modulus (100 Pa) alongside thousands of cells as they self-assemble into geometrically defined microtissues (spheroid and toroid shapes). Serial images of deformed HCMPs will be captured using a high-content confocal microscope and then computationally assessed to determine applied cellular forces. We will investigate differences for mesenchymal and epithelial cell types, as well as for integrin- vs. cadherin-coated HCMPs. Mechanistic understanding will be pursued using cytoskeleton-targeting drug treatments. This project will produce critical knowledge about how mechanics influences neotissue self-assembly and organization. By better understanding how cells exert forces on one another, we can begin to grasp how to direct these behaviors towards regenerative applications.
PI: Eric Darling, Associate Professor of Medical Science, Associate Professor of Engineering, Associate Professor of Orthopaedics
Co-PI: Haneesh Kesari, Assistant Professor of Engineering
Co-PI: Jeffrey Morgan, Professor of Medical Science, Professor of Engineering
Forecasting Patterns of Delirium and Early Recovery After Acute Stroke*
Delirium is common after acute stroke, and likely represents an impediment to recovery. However, the concrete manifestations of delirium comprise a spectrum, and it is unclear whether various patterns of symptoms may have differential effects on outcomes. Many of these symptoms are intimately connected, including arousal, attention, and activity level, and as a result, delirium phenotypes have been traditionally labeled as hyperactive, hypoactive, and mixed. Unfortunately, patients with hypoactive delirium are known to be underdiagnosed using standard screening tools, and the presence of pre-existing neurological symptoms only magnifies this challenge. We therefore propose an innovative approach aimed at diagnosing and categorizing delirium using wearable sensors capable of measuring activity on a granular scale. Activity data will then be analyzed using machine learning techniques to identify delirium phenotypes corresponding to patient activity patterns. We hypothesize that such patterns may also be predictive of early motor recovery after stroke, and we propose to apply similar machine learning techniques to identify activity-based phenotypes corresponding to post-stroke functional outcomes. We aim to leverage Rhode Island Hospital’s strength in clinical stroke care and Brown University’s expertise in biomedical informatics to build a collaborative partnership that will allow both institutions to become leaders in the field of translational stroke research. It is anticipated that the co-PIs of the proposed study will continue their collaboration to build a competitive research program based on novel data acquisition and analysis techniques. The insights obtained from this study will be used as crucial preliminary work enabling future NIH R01 funding applications.
PI: Michael Reznik, Assistant Professor of Neurology, Assistant Professor of Neurosurgery
Co-PI: Carsten Eickhoff, Assistant Professor of Medical Science, Assistant Professor of Computer Science
Enhancing Wound Healing Using Hydrogels for Localized Chemokine Delivery
Wound healing is an essential process in human health, and poorly healing wounds can lead to secondary infections, permanent disablement, and increased mortality. The Jamieson lab studies the role of the innate immune response in wound healing. We found that poorly healing wounds have a decrease in innate immune cells infiltrate. The immune suppression included lower levels of chemokines, which are essential to attract cells of the immune system. The wound healing rate could be restored by exogenous addition of the chemokines CXCL1 and CCL2. However, the materials used to apply chemokines had to be applied daily, which is not practical in a clinical setting. Therefore, we propose to develop chemokine delivering biomaterials that can be used to enhance wound healing. In the proposed work, we will build on expertise from PI Shukla’s lab on the development of hydrogel drug delivery materials and the expertise of PI Jamieson’s lab in the innate immune response and in vivo wound models, to develop and examine the efficacy of new chemokine releasing hydrogel materials. The mechanical properties of these hydrogels will be investigated along with the in vitro release and chemokine activity. Hydrogel formulations will be tested in vivo in two animal models of wound healing. Successful completion of this collaboration will pave the way for the development of a new research program using novel materials to improve wound healing. This research will be relevant to a variety of patient populations.
PI: Anita Shukla, Assistant Professor of Engineering, Assistant Professor of Molecular Pharmacology, Physiology and Biotechnology
Co-PI: Amanda Jamieson, Assistant Professor of Molecular Microbiology and Immunology
Building a Large Dataset of Articulated 3D Object Models
People spend a large percentage of their lives indoors: in bedrooms, living rooms, offices, kitchens, etc. The demand for virtual versions of these spaces has never been higher, with virtual reality, augmented reality, online furniture retail, computer vision, and robotics applications all requiring high-fidelity virtual environments. To be truly compelling, a virtual interior space must support the same interactions as its real-world counterpart: VR users expect to interact with the scene around them, and interaction with the surrounding environment is crucial for training autonomous robots (e.g. opening doors and cabinets). Most object interactions are characterized by the way the object's parts move or articulate. Unfortunately, it is difficult to create interactive scenes at the scale demanded by the applications above because there do not exist enough articulated 3D object models. Large static object databases exist, but the few existing articulated shape databases are several orders of magnitude smaller.To address this critical need, I propose to create a large dataset of articulated 3D object models: that is, each model in the dataset has a type and a range of motion annotated for each of its movable parts. This dataset will be of the same order of magnitude as the largest existing static shape databases. I will accomplish this goal by aggregating 3D models from existing static shape databases and then annotating them with part articulations. I will conduct the annotation process at scale using crowdsourcing tools (such as Amazon Mechanical Turk) by developing an easy-to-use, web-based annotation interface.
PI: Daniel Ritchie, Assistant Professor of Computer Science
Real-time View Synthesis for Robot Virtual Reality Teleoperation
Live virtual reality (VR) video is important for robotic teleoperation because the greater situational awareness and presence from VR help to increase robot control efficiency and effectiveness. However, in VR video, there is often a large difference between the freedom of movement afforded to the human operator by the VR tracking system and the freedom of view afforded by the camera system. This means that VR video often causes fatigue or sickness. To overcome this, light field cameras are required to help match the camera view to the VR motion parallax. We aim to develop a new real-time technique for view interpolation for VR robot teleoperation. A cheap and high-quality motion parallax solution will make VR video formats more able to meet the needs of complex robot remote control tasks.
PI: James Tompkin, Assistant Professor of Computer Science
Co-PI: Stefanie Tellex, Joukowsky Family Assistant Professor of Computer Science
Next Generation Brain Mapping of Meditative States: Toward Clinically-Viable Neurofeedback
There is a growing evidence base for the benefits of meditation on health, ranging from addiction to anxiety, depression, chronic pain and others. Much progress has been made in linking the quality of meditation to brain activity for the purpose of identifying neural mechanisms and developing neurofeedback for clinical use. This includes identification of key brain regions (e.g. the posterior cingulate cortex) associated with crucial aspects of the meditative experience (e.g. effortless awareness). This causal link between meditation and brain activity has been established by functional magnetic resonance imaging (fMRI), though the clinical utility of this modality is limited by prohibitive cost and low temporal resolution among others. We have been exploring source-estimated electroencephalography (EEG) as an alternative, though it has its own limitations, including proneness to artifact and low signal to noise ratios. Brown University is somewhat unique in having equipment that can bridge the gaps and capitalize on simultaneous strengths of fMRI and EEG by combining the two (simultaneous fMRI/EEG measurement). Our aims are to identify EEG correlates of PCC activity (as measured by simultaneous fMRI/EEG recording); and to develop a setup that can confirm that identified EEG correlates are specific to PCC activity and can be used for real-time neurofeedback. The methods and technology that will result from this project will benefit the Brown neuroscience research community, as it will lay the groundwork and foundation for simultaneous fMRI/EEG neurofeedback methods that can be used by cognitive neuroscientists across the university for studying a multitude of research questions.
PI: Judson Brewer, Associate Professor of Behavioral and Social Sciences
Co-PI: Remko van Lutterveld, Investigator in Epidemiology
Markers of Premature Biological Aging in Chronically Homeless Individuals*
Individuals that experience homelessness have higher age-adjusted mortality than domiciled counterparts. Multiple factors might contribute to these effects, but one understudied possibility is that exposure to homelessness may cause a phenomenon known as premature biological aging (PBA). PBA occurs when an individual’s biology suggests they are older than their years. Epidemiologic research, including our work, indicates that geriatric conditions in the chronically homeless are found at levels that suggest PBA of as much as 20 years, yet molecular studies have not been done. We must understand the effects of chronic homelessness on a molecular level to inform the development of targeted interventions (i.e., pinpointing the biological systems that contribute to increased mortality to identify new targets for treatment). We propose to fill key gaps in the literature and develop pilot data (i.e., big epigenetic data) to support an R01 grant application. Our primary study aims are to: 1): Examine associations of chronic and one-time short-term homelessness and premature biological aging (via DNA methylation and telomere length profiles), and 2) Identify which CpG sites are most differentially methylated by chronic and one-time homelessness. Our proposed work is highly innovative and would be the first in the country to examine PBA in individuals with prolonged exposure to an environmental stress (i.e., homelessness). We have assembled an interdisciplinary team of researchers from Brown and the Department of Veteran Affairs with a shared long-term goal of developing a research program centered on using state-of-the-art data analytics to improve health care for homeless individuals.
PI: Eric Jutkowitz, Assistant Professor of Health Services, Policy and Practice
Co-PI: John McGeary, Associate Professor of Psychiatry and Human Behavior
Co-Is: James Rudolph, Professor of Medicine, Professor of Health Services, Policy and Practice; Thomas O’Toole, Professor of Medicine; Hung-Teh Kao, Associate Professor of Psychiatry & Human Behavior (Research), Lorin Crawford, Assistant Professor of Biostatistics
Medications and the Risk of Motor Vehicle Crashes in Older Drivers
Motor vehicle crashes (MVCs) are a major source of morbidity and mortality for adults aged ≥65, resulting in 6,800 deaths and over 191,000 non-fatal injuries treated in emergency departments annually. Despite the common belief that prescription drug use is a leading cause of MVCs, after nearly three decades of research, data are scarce and controversy remains about the effects of medications on MVCs in older adults. A major barrier to progress has been the lack of detailed linked data on MVCs, prescription drug use, and age-related medical conditions. We propose to close this gap by linking detailed licensing and crash histories from over 2.3 million licensed drivers aged ≥65 to rich clinical and prescription drug data. Our aims are to 1) compile and link the New Jersey Traffic Safety Outcomes data to Medicare Parts A and D claims, and 2) describe the frequency and patterns of driving in older adults stratified by medication use and dose. Our proposal builds on Brown’s world-renowned reputation in aging and growing reputation in pharmacoepidemiology by expanding to a critical new area—transportation. Three products will result from the proposed initial effort: 1) a multi-institutional, multi-disciplinary research group with the Children’s Hospital of Philadelphia; 2) a unique data source that can be used to answer a wide array of medication-related and other research questions on transportation in older adults; and 3) conception of a research portfolio of topics centered on transportation and aging. Thus, we will be well-positioned to submit an R01 proposal responsive to National Institute on Aging Strategic Goals C and E.
PI: Andrew Zullo, Assistant Professor of Health Services, Policy and Practice, Assistant Professor of Epidemiology
Key Personnel: Nina Joyce, Assistant Professor of Health Services, Policy and Practice; Allison E. Curry, Assistant Professor of Pediatrics, Division of Emergency Medicine, University of Pennsylvania Perelman School of Medicine, and Senior Scientist and Director of Epidemiology and Biostatistics, Center for Injury Research and Prevention, Children’s Hospital of Philadelphia; Melissa R. Pfeiffer, Senior Biostatistician, Center for Injury Research and Prevention, Children’s Hospital of Philadelphia
*Big Data Collaborative Seed Award co-funded with the Data Science Initiative
Making Decisions with Manipulated Data: Applications to Credit Scoring in Developing Economies
Many decisions that were once made by humans are now made by computers. Prominent examples include the algorithms used to determine loan eligibility, to target promotions, and more recently, to inform bail and sentencing decisions. These systems typically build a predictive model that maps observed aspects of an individual’s behavior (e.g., past credit card transactions) to a predictive score that is then used to make a decision (e.g., whether or not to offer a loan). However, these models assume that once the system is in place, individuals will continue to behave in the same ways. If individuals strategically manipulate their behavior in order to improve their personal outcomes, the systems can become ineffective. This project seeks to launch a new research agenda to create algorithms that perform well in settings where the decision rule is transparent and individuals attempt to strategically manipulate their behavior. We will combine machine learning and mechanism design with practical calibration through lab-based testing and behavioral economic experiments. This agenda will advance Brown’s position in two directions: first, in the intersection between economics and computer science, particularly in big data and machine learning. Second, in development economics, for which the application of digital credit is important and in which Brown has been an early leader (Bjorkegren & Grissen, 2015).
PI: Daniel Bjorkegren, Assistant Professor of Economics
Database of Indigenous Slavery in the Americas
This project proposes to create the Database of Indigenous Slavery in the Americas (DISA), an easy-to-use, powerful, crowd-sourced database of indigenous slaves in the Americas. At its core will be an interface that registered users can access to enter biographical data they have on indigenous slaves. Once entered, this information would be added to a growing database that anyone could access directly by browsing through the entries and/or searching using various parameters. DISA will allow researchers to lift names off of the pages of obscure manuscripts and put them out into the wider online world where thousands of historians, researchers, students, tribal members, and families can use the information to reconstruct histories, chart networks, and make connections in ways that have never before been possible. It has the potential to transform the burgeoning humanities field of indigenous slavery scholarship.
PI: Linford Fisher, Associate Professor of History
Core team members: Elli Mylonas, Director, Center for Digital Scholarship; Brooke Grasberger, Ph.D. student (History); Marley-Vincent Lindsey, Ph.D. student (History); Juan Bettancourt-Garcia, Ph.D. student (History); Samuel Skinner, B.A. student (History); Paarul Sukanya Arulappa, M.A. student (Computer Science)
Biological and Life Sciences
Combined EEG and Pupillometry Measures of Language Processing as Markers for Early Detection of Alzheimer's Disease
Elderly individuals can display pathological changes preceding the onset of clinical Alzheimer’s disease (AD) by over a decade, and the ability to detect presymptomatic individuals at greatest risk for progressing to AD will be critical for the effective application of therapeutic strategies. This proposal exploits recent advances in cognitive neuroscience to develop novel probes that are sensitive to both the earliest cognitive changes in AD and the compensatory processes moderating these changes, and that can be utilized as a neurocognitive “stress test” for early detection of AD. The proposed research will systematically assess the dynamics of automatic and controlled language processing in cognitively normal elderly with high or low biomarker risk of AD, using a novel combination of electrophysiological (EEG) and pupillometry measures. EEG allows for on-line measurement of automatic and controlled components of natural language processing, while pupillometry allows for the simultaneous assessment of the cognitive effort or arousal needed for task performance. This research should not only help improve identification of individuals at risk for developing AD, but should also contribute to the general understanding of changes in the arousal and cognitive control systems in healthy and pathological aging.
PI: William Heindel, Professor of Cognitive, Linguistic and Psychological Sciences
Key Personnel: Nicole Amichetti, Visiting Scholar in Cognitive, Linguistic and Psychological Sciences; Brian Ott, Professor of Neurology; Elena Festa, Lecturer in Cognitive, Linguistic and Psychological Sciences
Instrumentation for Specimen Vitrification for Electron Cryo-Microscopy at Brown University
Due to recent developments in both hardware and software, electron cryo-microscopy (cryo-EM) has become a remarkably versatile and powerful structure determination technique that can be applied to diverse macromolecular species and assemblies. On one hand, imaging under the electron microscope can be combined with powerful algorithms for averaging and classification, which essentially constitute a process of purification in silico, thus enabling structural analysis of complex and heterogeneous species that would not be otherwise amenable to structure determination by traditional techniques, such as crystallography or NMR. On the other, increased beam coherence, stability and automation as well as new detectors and strategies for correcting for beam-induced motion of specimens have revolutionized the practice of electron microscopy, extending its resolution limit close to what is typically attained using X-ray diffraction. Specimen preparation, however, remains the rate-limiting step, and a key element of this process is the vitrification of the macromolecule of interest at low temperatures. Here we propose the acquisition of a high-performance Vitrobot plunge-freezing instrument that is absolutely necessary for initiating the EM structure determination workflow on site and with minimal delays or disruptions to the macromolecular specimen under investigation. We anticipate interest from a large number of investigators, with expertise in diverse areas of biology, but with a common, strong interest in using structural information to answer mechanistic questions in biology.
PI: Alexandra Deaconescu, Assistant Professor of Molecular Biology, Cell Biology and Biochemistry
Co-PI: Gerwald Jogl, Associate Professor of Biology
Role of Matrix Metalloproteases in Neurodevelopmental Disorders
Autism spectrum disorder (ASD) is thought to result from low-level deficits in synaptic function during early brain development that can cascade into higher order cognitive deficits. The link between synaptic dysfunction and complex behavior is not well understood. We employ a multidisciplinary approach to study the development of neural circuits at multiple levels of analysis, ranging from synapses to behavior, using the development of Xenopus laevis tadpole visual system as a model. We recently found that tadpoles exposed to valproic acid (VPA), an antiepileptic drug associated with increased incidence of autism when exposed prenatally, during early development, results in hyperconnected neural circuitry that leads to behavioral phenotypes consistent with hyperexcitability. Although the action of VPA is strongly conserved across vertebrates, its mechanism of action is unknown. VPA is a histone deacetylase inhibitor known to misregulate gene expression. Using a genetic screen, we identified matrix metalloprotease nine (MMP9) as a gene strongly upregulated after VPA exposure. MMP9 regulates extracellular matrix function and is strongly implicated in neural development. The experiments in this proposal will integrate experimental techniques ranging from electrophysiology, functional imaging, and behavioral analysis to test the hypothesis that early exposure to VPA results in abnormal neural circuit development due to upregulation of MMP9 expression. Such a comprehensive analysis of MMP9 function in multiple aspects of brain development has not been conducted and would significantly increase our fundamental understanding of MMP9 and other metalloproteases in brain development, providing fundamental insights into the etiology of ASD and other neurodevelopmental disorders.
PI: Carlos Aizenman, Professor of Neuroscience
Role of intestinal epithelium specific retinoic acid signaling in regulating host-microbe interactions.
Intestinal epithelium and mucus layer form a physico-chemical barrier crucial for gut homeostasis. Impaired gut barrier function is a hallmark of inflammatory bowel disease. Intestinal epithelial cells (IECs) are at the frontline of host-microbe interactions in the gut, yet how their biology is regulated by dietary cues is poorly understood. Vitamin A and its key metabolite retinoic acid (RA), are crucial regulators of gut immune homeostasis. Using a mouse model that expresses a dominant negative retinoic acid receptor exclusively in IECs (dnRARVillin-Cre) we establish a novel role for RA signaling in regulating the mucus barrier. We observe that the absence of RA signaling in colonic epithelium resulted in significant increase in mucus layer thickness and more goblet cells. This indicates a crucial role for RA in regulating goblet cell function. Furthermore, we show that dnRARVillin-Cre mice have a diminished sensitivity to chemically induced colitis. Quantitative analysis uncovered that transcription and protein activation of key pro-inflammatory cytokine IL-18 was severely impaired in epithelium of dnRARVillin-Cre mice. IL-18 has previously been shown to act as a negative regulator of goblet cell function in the intestine. I hypothesize that dietary vitamin A is a key regulator of goblet cell function and host-microbe interactions in the gut. The aim of this study is to delineate the mechanistic link between RA signaling and IL-18 in the intestinal epithelium and its implications for gut barrier integrity. In alignment with Brown’s vision of translational research, this study could provide clues for dietary and pharmacological interventions for IBD.
PI: Shipra Vaishnava, Assistant Professor of Molecular Microbiology and Immunology
Co-PI: Namrata Iyer, Postdoctoral Research Associate in Molecular Microbiology and Immunology
Mechanistic insights into the role of cellular senescence in neonatal hyperoxic lung injury
Premature infants are often exposed to high concentrations of oxygen as a lifesaving measure. Unfortunately, this can result in lung injury that persists into adolescence and adulthood. This injury is replicable in neonatal mice exposed to hyperoxia. We have shown that neonatal mice (>12 hours old) exposed to hyperoxia for 3 days have markedly increased numbers of senescent cells compared to air exposed controls. After recovery from hyperoxia in room air for up to 60 days, the lung alveolar epithelium became simplified, however, the number of senescent cells were significantly reduced vs. air controls. This suggests that the senescent cells originally observed were targeted for immune clearance. If senescence targets lung progenitor cells, this could prevent normal lung recovery. Metabolic shifts from glycolysis to oxidative phosphorylation play important roles in cellular senescence, and p53 signaling pathways regulate these shifts. Whether this is involved in hyperoxia-mediated senescence in the neonatal lung is unknown. We hypothesize that hyperoxia causes metabolic shifts, leading to lung epithelial cell senescence and simplified alveolarization. Our specific aims are 1) to uncover the impact of hyperoxia on markers of cellular senescence in the neonatal lung and 2) to determine whether metabolic shifts dictate hyperoxia-mediated senescence in the neonatal lung. These studies should allow us to understand how hyperoxia regulates senescence and how this impacts later lung injury and repair. These studies will also allow us to devise therapeutic interventions that could prevent neonatal hyperoxia-mediated lung disease in neonates by targeting metabolism.
PI: Phyllis Dennery, Sylvia Kay Hassenfeld Professor of Pediatrics and Molecular Biology, Cell Biology and Biochemistry
Co-PI: Jill Kreiling, Associate Professor of Molecular Biology, Cell Biology and Biochemistry (Research)
Regulation of neural stem cells by the BMP co-receptor MuSK
The brain harbors neural stem cells (NSCs) that generate neurons and glial cells throughout life. These adult-born neurons are important for normal brain function and plasticity and are also being explored as a means to repair the brain. A key unknown is the mechanism mediating NSC fate. BMPs (Bone Morphogenic Proteins) regulate two critical NSC decision points: 1) quiescence, where proliferating stem cells exit the cell cycle and return to a replenish a reserve pool that can supply fresh stem cells; and 2) differentiation into mature progeny - oligodendrocytes, astrocytes or neurons. The goal of this proposal is to test the role of the newly discovered BMP co-receptor MuSK in these NSC cell fate decisions using both cell culture and in vivo systems. The Webb lab is expert at NSC biology and has generated extensive tools and data on BMP-regulated quiescence and differentiation. The Fallon lab recently discovered that MuSK is a BMP co-receptor that quantitatively and qualitatively regulates BMP-mediated transcription in myogenic cells. The Fallon lab has generated mouse lines expressing MuSK lacking the domain required for high affinity BMP binding (‘MuSK-Ig3-/-’). Working together the Co-PIs have already established that freshly isolated adult NSCs express MuSK RNA and protein. On a larger scale, this collaboration is designed as a catalyst to bring together several labs at Brown with shared interests in BMP/TGFß signaling.
PI: Ashley Webb, Assistant Professor of Molecular Biology, Cell Biology and Biochemistry
Co-PI: Justin Fallon, Professor of Medical Science and Psychiatry and Human Behavior
Using machine vision to automate behavioral analysis of C. elegans
Here, we combine our expertise in computer-vision and behavioral genetics to move forward with development of a high-content, computer-vision system for analysis of C. elegans behavior. The automated analysis system will be generally applicable to any small animal moving in a one-dimensional plane, will yield novel insights into behavior in C. elegans ALS models and sleep, and will provide critical preliminary results for NIH applications under review or planned by the co-investigators. The project is based on synergy from very different fields. Dr. Thomas Serre (Brown CLPS) and Dr. Anne Hart (Brown Neuroscience). Dr. Serre is a leading expert in the development of high-content, computer-vision systems. He worked with his student to develop the prototype analysis system used to generate preliminary results herein. Dr. Hart is a leading expert in C. elegans behavior. She worked with her students to obtain C. elegans behavioral data and validate the results of the preliminary computer-vision analysis. Our long-term goals are to 1) develop the versatile open-source, computer-vision behavioral analysis system proposed here 2) optimize the system to allow real-time, accurate scoring of behaviors, without manual intervention or annotation and 3) to establish an online resource/database at Brown University that will allow any researcher to easily reuse and repurpose videos, images and analysis results. This will dramatically raise the stature of Brown University in the field.
PI: Anne Hart, Professor of Neuroscience
Co-PI: Thomas Serre, Associate Professor of Cognitive, Linguistic and Psychological Sciences
Making an Impact: Dynamic Free-Surface Interactions
When small objects are gently deposited onto an air-water interface, their weight can be supported by the effects of surface tension. Bench-top demonstrations of this effect are simple to realize and are often one of the first experiments by which a student is introduced to the remarkable influence of surface tension at small scales. Recently, considerable work has been devoted to the statics of small particles supported at interfaces. However, less attention has been given to the dynamics of such particles at fluid interfaces, despite the broad relevance to numerous natural, scientific, and industrial systems. As an initial step towards advancing the current understanding of such dynamic interactions, we plan to conduct a detailed exploration of the impact of hydrophobic spheres onto an air-water interface. The proposed research direction includes both an experimental component conducted at Brown, and a complementary theoretical component developed with international collaborators at the University of Bath. This foundational work will facilitate future work in our lab aimed at gaining a more general understanding of the interactions of solid structures with liquid interfaces in scenarios where surface tension effects are dominant.
PI: Daniel Harris, Assistant Professor of Engineering
Development of Materials with Designed Meso-scale Architectures for Dynamic Loading
We propose to develop a research program on developing new high-performance structural materials with designed meso-architectures that will have much higher resistance to the dynamic failure mode of adiabatic shear localization (ASL). Structures and materials subjected to dynamic loading often fail by ASL, which is a thermomechanical instability. Most of the existing work to-date on the dynamics of ASL treats the material as a homogeneous continuum with effective mechanical and thermal properties. However, it is known that alloys with nominally same composition but different microstructures can result in different resistance to failure by ASL; so, clearly and unsurprisingly, the material meso-architecture plays a crucial role in determining the resistance to ASL. However, there have been no studies on understanding the dynamics of the interaction between a propagating ASL and the material’s meso-scale architecture; primarily because of experimental difficulties associated with measuring strain fields at high-spatial (~ microns) and high-temporal resolutions (micro-second) simultaneously. By using a new and unique experimental capability developed in the PI’s lab that fills this gap in experimental diagnostics, we propose a systematic, combined experimental-theoretical study that aims to (i) understand the basic physics and mechanics of interaction between a propagating ASL and model meso-architectures; (ii) design, fabricate and demonstrate the superior performance “periodic layer” meso-architectures. The proposed research program, along with the newly developed experimental and computational capabilities place Brown researchers in a strong position among their peers to attract external grant support to grow the program.
PI: Pradeep Guduru, Professor of Engineering
Co-PI: Haneesh Kesari, Assistant Professor of Engineering
Gravitational waves -- the new window to the universe
The spectacular discovery of gravitational waves (ripples in spacetime) less than 2 years ago opened a completely new window to the universe. This proposal will build upon preliminary work by the PI and explore how gravitational waves can be used to help understand the formation of baryonic structure in the universe as well as probe fundamental physics problems in cosmology.
PI: Savvas Koushiappas, Associate Professor of Physics
Green Chemistry Synthesis of PBO-Type Rigid Polymers
Poly(p-phenylene-2,6-benzoxazole) (PBO) represents a class of well-known rigid polymers that have both excellent thermal stability and remarkable tensile strength and modulus (1.6 times that of Kelvar). These exceptional properties place PBOs among the strongest organic polymers for a wide number of applications such as ballistic fiber materials, smart electronic textiles, and flame resistance materials. However, the conventional approach to PBO synthesis via polymerization of diaminobenzenediol and terephthalic acid requires polyphosphoric acid (PPA) as the catalyst. As a result, the final PBO product inevitably contains traces of PPA that can also catalyze the hydrolysis of the benzoxazole ring in PBO in a humid environment. This, combined with the effect of UV-irradiation, is known to lead to rapid polymer degradation, causing the uncontrolled loss of mechanic strength and serious mechanical failures of the PBO materials. Combining three PI’s expertise in nanoparticle catalysis, organic reactions, and mechanical property studies, this joint proposal intends to develop a green chemistry approach to PBOs with a controlled degree of polymerization, enhanced chemical stability against hydrolysis and/or UV-irradiation, and robust mechanical strength under various humidity conditions. With the OVPR seed support, the three PIs’ efforts will evolve into a new multi-disciplinary research direction with chemistry, materials, mechanics and computations involved. The research will help to leverage both chemistry and mechanical engineering profiles in catalysis and materials research.
PI: Shouheng Sun, Vernon K. Krieble Professor of Chemistry, Professor of Engineering
Co-PI: Christopher Seto, Associate Professor of Chemistry
Co-PI: Pradeep Guduru, Professor of Engineering
Health Effects of Electronic Cigarettes for Harm Reduction in Smokers with HIV
Cigarette smoking is more prevalent in persons living with HIV (PLWH), when compared with the general population, and is linked to increased morbidity and mortality. HIV-infected smokers have increased rates of cardiovascular disease, pulmonary disease, and lung cancers. While most HIV-infected smokers report a strong desire to quit, they are significantly less likely to quit when compared to general population smokers. Many choose a goal that includes occasional or controlled tobacco use, perhaps a reflection of the harm reduction model that is emphasized in many substance use and HIV risk reduction programs. Electronic cigarettes (EC), may reduce harms related to combustible cigarette (CC) smoking, and may provide HIV-infected smokers with a needed alternative. However, little is known about the health effects of EC in PLWH. Our specific aims are to examine: 1) the feasibility and acceptability of EC distribution in PLWH; 2) the effect of EC use on smoking behaviors; and 3) the change in cardiopulmonary symptoms and biomarkers in smokers who transition from CC to EC use. We will enroll 12 HIV-infected smokers and will provide free EC for 8-weeks. At weekly visits, we will assess EC and CC use, cardiac/respiratory symptoms, and perceived safety/harm of EC use. At BL and week 8, we will measure inflammatory biomarkers and markers of tobacco toxicant exposure. At week 12, we will assess change in EC or CC use, quit line contact, and quit attempts. This study will be the first to examine the health effects of EC on HIV-infected smokers.
PI: Patricia Cioe, Assistant Professor of Behavioral and Social Sciences
Co-Investigators: Christopher Kahler, Professor of Behavioral and Social Sciences; Jennifer Tidey, Professor of Psychiatry and Human Behavior and Behavioral and Social Sciences (Research)
Immunomethylomics of Head and Neck Cancer Survivorship
Head and Neck Squamous Cell Carcinomas (HNSCCs) are devastating upper airway tumors that are associated with an immunosuppressive network impacting the tumor microenvironment, bone marrow and the peripheral blood compartments. The development of novel biomarkers of cancer immunity have not kept pace with breakthroughs in our understanding of cancer-associated inflammation and its relationship with abnormal hematopoiesis and the production of immunosuppressive leukocyte populations. This proposal, targeting pilot funding, aims to fund the acquisition of additional pilot data. In the parent application we address the gap in clinically applicable immune biomarkers by first developing unique immuno-methylomic tools to identify aberrant peripheral immune cell populations, followed by the application of such tools for studying HNSCC survivorship as well as to explore the application of these biomarkers in ongoing clinical immunotherapy trials. The proposed R01 will draw from one large cohort of HNSCC patients recruited over separate, consecutive 5- year grant cycles cases whose tumors have been extensively characterized using cutting edge molecular analyses. As new immunotherapies are developed for HNSCC, it is crucial to mediate the effects of the host’s compromised immune system. The generation of additional data will further demonstrate to reviewers that epigenetic techniques for immune profiling will provide biomarkers that are useful both in assessing immune status and in addressing mechanisms of immune modifiers.
PI: Karl Kelsey, Professor of Epidemiology and Pathology and Laboratory Medicine
"Right-sizing" opioid prescription post- cesarean delivery and hysterectomy: Balancing excess medication and patient pain control
Opioids are mainstay treatment for acute pain after surgery, including cesarean delivery (CD) and hysterectomy. Approximately 1.8 million women have a CD or hysterectomy each year; Most consume a fraction of opioids prescribed and do not dispose of unused opioids properly. This project addresses the critical need to decrease prescription opioids available for misuse using a collaborative approach between interdisciplinary investigators with complementary expertise to create and evaluate a multilevel, theory-based intervention (physician and patient-targeted) designed to facilitate the provision of “right-size” prescriptions (reduce left-over opioids while maintaining pain control) following CD or hysterectomy. The specific aims are 1: To conduct formative research with prescribing physicians, nurses, and patients; 2: To use this information to create two web-based interventions; a) for prescribers encouraging right-size opioid prescribing and b) for CD and hysterectomy patients to encourage appropriate use and excess medication disposal; 3: To pilot test the new interventions a) To assess implementation; b) To estimate efficacy by comparing (pre- vs. post-intervention) amount of 1) opioids prescribed, 2) prescribed opioids not consumed; 3) pain scores; and 4) appropriate patient disposal of excess medications; 4: To prepare and submit an NIDA/NIH application based on these data. An effective intervention to promote “right-size” opioid prescriptions after CD and hysterectomy has the potential for extrapolation to other surgical settings to widely address optimal opioid prescribing post-operatively, which would advance Brown University’s position as a center of excellence in addressing the opioid epidemic.
PI: Patricia Risica, Associate Professor of Behavioral and Social Sciences
Associate Professor of Epidemiology
Co-PI: Kristen Matteson, Associate Professor of Obstetrics and Gynecology
Co-Investigators: Brandon Marshall, Associate Professor of Epidemiology; Theresa Shireman, Professor of Health Services, Policy and Practice
Assembling Comprehensive, Fine-scale Data on Historical Transformations in Land Use
Despite the growing availability of big data in many fields, historical data on social phenomena are often not available due to a lack of automated and scalable approaches for collecting, digitizing, and assembling them. We have developed a data-mining method for extracting tabulated, geocoded data from printed directories. In preliminary studies, we validated the method on scanned images of the annual Rhode Island Manufacturing Directory, which record nearly 60 years of industrial land use. The resulting dataset can be used for socioenvironmental analyses of industrialization and urbanization at a resolution that was not previously possible, revealing patterns of industrial churning and accumulated risk of industrial hazards. Through seed funding, we propose to scale our data collection efforts to an ideal and complementary data source for commercial and residential land use: phone books. Combining data from manufacturing directories and phone books, we will build a comprehensive dataset for land use in the Providence metropolitan area, and use it initially to test theories of land-use transformation. The successful application of our method to one metropolitan area will demonstrate the feasibility of scaling it to multiple metropolitan areas of interest across the United States. Such a data resource, encompassing nationwide land-use transformations over multiple decades, would be broadly valuable to social scientists interested in questions of urban-scale spatial processes.
PI: Scott Frickel, Associate Professor of Sociology and Environment and Society
Co-PI: Mark Howison, Director of Data Science, Computing and Information Services
Key Personnel: David Berenbaum, Lead Data Scientist, Computing and Information Services; Ashley Lee, Data Science Associate, Computing and Information Services; Thomas Marlow, Graduate Student, Sociology
The Field of the Chinese State: An "Archive to Article" Project
This project is a new digital platform for large-scale, descriptive, open-access information on the evolution of the Chinese government from roughly 400 years ago to today. It departs from most digital humanities endeavors in that it does not assume a “one-text, one-world” approach, but seeks to exploit the potential of digital tools and collaborative methods to solve a problem of incomplete corpora and inconsistent digitization. We envision a closed collaborative environment that will help scholars apply consistent metadata, tagging, markup, citation and other common tools to documents that range from raw archival material to idiosyncratic databases to the search output of digital corpora. The open-access end point of such work will be an ever-evolving handbook of institutions underpinning the development of modern China. This is especially important to modern Chinese studies for two reasons. First, the sources are inherently more disparate and numerous than those in pre-modern East Asian Studies, which has seen the most sophisticated digital humanities work. Meanwhile, political and logistical obstacles have hindered the rendering of modern archives digitally and publicly available. Second, intellectual siloing has reduced long-term institutional analysis of the Chinese state even as information accrues and public interest in the subject increases. We anticipate, however, that the intellectual principles and practical application of this platform will be of interest to programmers, historians, and digital scholars beyond the China field. For Brown, this project would be an opportunity to push digital scholarship in new directions and join a major growth area of Asian studies.
PI: Rebecca Nedostup, Associate Professor of History
Co-PI: Maura Dykstra, Assistant Professor, History, California Institute of Technology
Technical Advisor: Ian Matthew Miller, Assistant Professor of History, St. John's University
Rapid self-testing to prevent fentanyl overdose among young people who use drugs
Drug overdose is among the most pressing public health problems in the United States. Greatly exacerbating the nation’s overdose crisis has been the emergence of non-pharmaceutical fentanyl (NPF), a highly potent synthetic opioid mixed in heroin and other drugs. Multiple states in regions throughout the country are reporting an unprecedented surge of fentanyl-involved overdose deaths. In this pilot study, we will characterize the prevalence, knowledge of, and perceptions towards NPF exposure among heroin and counterfeit pill-using young adults (the age group most affected by NPF). Second, we will test the feasibility and acceptability of a “take home” fentanyl self-testing intervention to increase overdose risk reduction behaviors and improve uptake of naloxone, an opioid overdose antidote. We will recruit a community-based sample of 40 young adults aged 18 to 35 who use heroin, counterfeit prescription pills, or inject drugs. All participants will complete structured interviews and will provide urine samples to test for recent NPF exposure at baseline. Then, participants will receive 5 “take home” rapid screens, which detect NPF metabolites in urine and will be used to study participants to identify when they have been exposed to NPF. Participants will be asked to submit their results in real-time through an overdose prevention and surveillance website, www.PreventOverdoseRI.org. In sum, this research will significantly enhance public health efforts to prevent, identify, and respond to spikes in fentanyl overdose among young adults.
PI: Brandon Marshall, Manning Assistant Professor of Epidemiology
Co-Is: Traci Green, Adjunct Associate Professor of Emergency Medicine and Epidemiology, and Deputy Director of the Boston Medical Center Injury Prevention Center; Josiah Rich, Professor of Medicine and Epidemiology, and Director of The Center for Prisoner Health and Human Rights; Scott Hadland, Assistant Professor of Pediatrics, Boston University School of Medicine; Edward Bernstein, Professor of Emergency Medicine, Boston University School of Medicine
Consultant: Jane Buxton, Professor of Medicine, University of British Columbia and the Harm Reduction Lead/Physician Epidemiologist at the British Columbia Centre for Disease Control
Leveraging heterogeneity across screening centers in the National Lung Screening Trial to inform screening policies
Lung cancer screening with low-dose computed tomography (LDCT) has gained prominence as a promising intervention to reduce lung cancer mortality. Although recommended as a preventive service with Medicare coverage, the high rate of false-positive findings may be a barrier to its widespread implementation. Therefore, stricter positivity thresholds are applied in clinical practice but their impact on patient-relevant outcomes (clinical utility) is unknown. Here we propose to evaluate the tradeoffs between different LDCT-positivity thresholds and screening outcomes using data on more than 50,000 participants in the National Lung Screening Trial (NLST). We will innovatively apply evidence synthesis methodology to leverage the heterogeneity in LDCT diagnostic performance and health outcomes across the 33 centers in the NLST. This evidence can inform policy decisions about the tradeoffs between benefits and harms of LDCT screening. This Seed grant will set the foundation for a high-impact Brown-based research program focused on the efficient implementation of lung cancer screening in pragmatic healthcare settings. We will build a strong network of collaborations across Brown-affiliated schools and hospitals as well as with the Intramural Program of NIH. We will capitalize on research strengths unique to Brown in health services, evidence synthesis, epidemiology and biostatistics. Consequently, our program will make Brown a leader in research to inform national policy decisions and clinical practice guidelines for lung cancer screening.
PI: Orestis Panagiotou, Assistant Professor of Health Services, Policy and Practice (Research)
Co-PI: Ilana Gareen, Associate Professor of Epidemiology (Research)
Co-Is: Linda Nici, Professor of Medicine (Clinical); Thomas Trikalinos, Associate Professor of Health Services, Policy and Practice, and Director of the Center for Evidence Synthesis in Health
Collaborators: Christine Berg, Senior Advisor, Office of the Director, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH; Hormuzd Katki, Senior Investigator, Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH
Gravitational Lensing and X-ray Survey of the Local Universe
The two biggest unsolved mysteries in Cosmology concern the nature of Dark Matter and Dark Energy, two different and poorly understood substances that together make up more than 95% of the energy density of the Universe. Studies of clusters of galaxies provide the opportunity to investigate the nature of both dark matter and dark energy. Clusters of Galaxies are the largest structures in gravitational equilibrium in the Universe. Because they are the largest reservoirs of dark matter, clusters are a great place to investigate the nature of dark matter, and particularly dark matter-dark matter interactions. At the same time, because clusters are so large, their formation history is sensitive to dark energy. Technological developments of the past three years, in the form of new large-format cameras and the development of software tools to combine data from multiple telescopes, now finally make it possible to conduct a compete study of the galaxy clusters in the nearby Universe. Here, I request funds to support the collection and analysis of all cluster data already serendipitously acquired in the archives of the world's major observatories. The analysis will lead to: 1) The development of a "survey-class'' proposal to the US (and possibly Canadian) national observatories, requesting 50-100 nights of telescope time over the following three years; 2) the organization of a multi-institution collaboration to analyze the results and obtain X-ray satellite observations (and funds associated with those); and 3) a major proposal to the NSF to fund the analysis of this data.
PI: Ian Dell'Antonio, Professor of Physics
Automated Sleep Recommendations Over a 10 Year Sleep Study
SleepCoacher is an automated system to help you achieve that by monitoring your sleep behaviors, guiding you towards better sleep quality through self-experiments that happen while you sleep.
PI: Jeff Huang, Assistant Professor of Computer Science
Co-PIs: Julie Boergers, Associate Professor of Psychiatry and Human Behavior and Associate Professor of Pediatrics; John McGeary, Associate Professor of Psychiatry and Human Behavior; Nicole Nugent, Associate Professor of Psychiatry and Human Behavior (Research), Associate Professor of Pediatrics (Research); Paul Pirraglia, Associate Professor of Medicine; Karen Woolfall-Quinn, Associate Professor of Medicine (Clinical)
Communication Theory for Chemical Sensing Networks
Detecting airborne chemicals in natural environments is challenging due to the small amounts of target chemical available to the sensor, comparatively high background interference, and highly complex airflows. We propose to develop systems for distributed chemical sensing which employ communication theory to intelligently combine signals from a distributed network of low cost wireless chemical sensor nodes. Perhaps the most vivid application of such a system would be the identification of vapors from improvised explosive devices in public spaces. We will develop prototypes which allows for the evaluation of new signal processing approaches that take advantage of temporal and spatial correlations to improve the quality and variety of information that can be gleaned from distributed chemical sensors. The PIs have complementary expertise to support this project. Jacob Rosenstein develops advanced embedded electronic systems for biomedical and chemical sensory interfaces. Christopher Rose is an information theorist who has a special interest in non-traditional communications mediums. This seed will support a highly interdisciplinary project, combining elements of mathematics, electronics, chemistry, environmental science, and fluid mechanics. We feel that this project will put Brown in a very strong position to leverage all of its existing expertise in these areas, and to open up a new avenue of research.
PI: Jacob Rosenstein, Assistant Professor of Engineering
Co PI: Christopher Rose, Professor of Engineering
Walkerbot: Mobility and Connection for an Aging Population
Both maintaining connections to loved ones and maintaining a level of physical activity present challenges to the elderly. The Walkerbot is a robot which rises to those challenges. Starting as a traditional telepresence robot, the Walkerbot can be driven or navigate semi-autonomously to an elderly person. It then can transform into a power assisted walker, while keeping the screen visible. This enables the elderly person to continue the conversation while walking with the robot. This could have potential both in institutional care settings but also in medical facilities to help with patient transport and rehabilitation exercise. The Walkerbot would also improve mobility by incorporating obstacle detection and fall detection. Additional medical sensors, blood pressure, oxygen levels etc could be attached in rehabilitation settings.
PI: Stefanie Tellex, Assistant Professor of Computer Science
Co-PI: Ian Gonsher, Adjunct Lecturer in Engineering
Collaborator: Elizabeth Phillips, Postdoctoral Research Associate in Cognitive, Linguistic and Psychological Sciences
Biological and Life Sciences
Using Single Cell Biophysics and Shear Wave Ultrasound Elastography to Measure Cancer Mechanics Across Multiple Scales
In vitro studies have shown that physical properties of the extracellular matrix can be used to control stem cell differentiation, cancer progression, and tissue regeneration. In these studies, immortalized cell lines were often cultured on synthetic matrices with mechanical properties that mimic biological tissues. These controlled studies elegantly demonstrate the importance of matrix stiffness in inducing malignant cell phenotype. The Dawson lab also showed epithelial-mesenchymal transition in breast cancer cells was sufficient to alter cytoskeletal mechanics and increase cell-exerted traction forces. We assume that these biophysical changes in cancer cells, which were associated with increased motility, proliferation, and chemoresistance, will be predictive of more invasive disease; however, this finding has never been demonstrated in patient-derived cells. The proposed studies will use biophysical tools to characterize the mechanical phenotype of cells isolated directly from tissues that have undergone pathological stiffening. Shear wave ultrasound elastography, a non-invasive imaging technique that uses acoustic radiation forces to map tissue elasticity at mm length scales, will be used to characterize tissue stiffness prior to biopsy. Quantitative single cell biophysical analysis will then be used to characterize the mechanical phenotype of cells isolated from biopsy samples. With this approach we should be able to determine if changes in the mechanical phenotype of cancer cells are associated with local tissue stiffening and cancer progression. The goals of this collaborative proposal are aligned with NCI goals for the Physical Sciences in Oncology Program; seed grant funding will allow us to collect essential data for PS-ON submission.
PI: Michelle Dawson, Assistant Professor of Molecular Pharmacology, Physiology, and Biotechnology
Co-PIs: Michael Beland, Associate Professor of Diagnostic Imaging; Derek Merck, Assistant Professor of Diagnostic Imaging (Research) and Assistant Professor of Engineering (Research)
Mechanisms in mitochondrial metabolism in brain development and health
We have discovered mutations in a mitochondrial enzyme, glutamate pyruvate transaminase 2 (GPT2) that are associated with a novel neurological disorder. In our recent paper, using both metabolomics and direct isotope labelling methods, we identify metabolic defects in brains from a Gpt2 mutant mouse model. In this proposal, we will generate important preliminary data in a Gpt2 mouse mutant. These studies are innovative, as neurometabolism has scarcely been investigated in the context of brain development. This research is strongly in line with the OVPR Research Seed funding mechanism as we will generate data for new research proposals. We will also develop important collaborations for this research: at Brown, with Dr. Phyllis Dennery’s laboratory; and at UT Southwestern/HHMI, with Dr. Ralph DeBerardinis’ laboratory. Overall, this research has the potential for substantial impact on: (1) the discovery of linkages between mechanisms in mitochondrial metabolism and postnatal brain development with broad relevance to mechanisms in brain diseases; and (2) the development of new approaches to screening and prevention of disease.
PI: Eric Morrow, Associate Professor of Biology and Associate Professor of Psychiatry and Human Behavior
Collaborator: Phyllis Dennery, Sylvia Kay Hassenfeld Professor and Chair of Pediatrics and Professor of Molecular Biology, Cell Biology and Biochemistry
The role of sleep in visual plasticity
The purpose of the current proposal is to collect a preliminary data with which to write an NIH R01 competitive renewal proposal to advance the understanding of visual plasticity. A prevailing view is that the role of sleep in plasticity is to merely enhance plasticity states already triggered by training. However, we challenge this prevailing view and propose the alternative possibility that even without prior training, plasticity states occur in early visual areas specifically during sleep stage N3. To test this hypothesis, using magnetic resonance spectroscopy during sleep, we will measure an excitatory-inhibitory (EI) ratio, which is defined by the ratio of excitatory/inhibitory neurotransmitters, in early visual areas. An EI ratio is correlated with the degree of plasticity in early visual areas. Thus, by measuring EI ratios during sleep, we can examine the degree of plasticity states without measuring performance improvement. If preliminary data supports the hypothesis, this will suggest that there is sleep-based plasticity independently from training-based plasticity and significantly increase the probability of having the R01 competitive renewal funded. In that event, the Brown’s reputation in the field of in sleep and visual plasticity would be greatly enhanced.
PI: Yuka Sasaki, Associate Professor of Cognitive, Linguistic and Psychological Sciences (Research)
Collaborator: Takeo Watanabe, Fred M. Seed Professor of Cognitive, Linguistic, and Psychological Sciences
Developing a model to assess the effect of compromised BMP4 signaling and smoke exposure on craniofacial development
Three percent of all newborns have a birth defect yet we know the cause of these defects in less than 20% of cases. It is now evident that developmental anomalies likely arise from the interaction of multiple factors, i.e., a single gene dysfunction may be enhanced by an environmental insult or an additional gene mutation. Population level epidemiological studies have identified environmental risk factors for various conditions and diseases, but the identification of discrete gene-by-environment interactions has been difficult. Large-scale studies in Drosophila have been successful in identifying specific gene-environment interactions, but few have been done in mammals. Fewer still have focused on gene-environment induced birth defects and most have not focused on mechanism. The BMP cell signaling pathway is known to be involved in craniofacial development and a specific mutation hBMP4-R612Q has been associated with cleft lip/palate, the most common birth defect worldwide. We hypothesize that the efficacy of BMP signaling is compromised by exposure to tobacco smoke. We found that BMP4 signaling output is reduced when cells in culture are exposed to cigarette smoke extract (CSE) and that hBMP4-R612Q activity is further compromised by CSE. Our overall objective is to extend these findings to an in vivo system to reveal the cellular and molecular mechanisms underlying palate outgrowth and closure, as well as to develop a sensitized system to assess maternal smoke exposure. We intend this project to lay the groundwork for future identification of factors to reduce or eliminate the number of birth defects.
PI: Kristi Wharton, Professor of Biology
Unraveling Actinide Structure in the Environment: An Integrated Theoretical, Computational, and Spectroscopic Approach*
One of the enduring legacies of the nuclear age is the tons of nuclear waste that have been released into the environment. Removing these largely actinide-containing wastes requires a thorough understanding of what actinide (U, Pu, Np, etc.) complexes form in different chemical settings. Because of the complexities posed by 5f-electron chemistry/physics, predicting the structure, energetics, and reactivity of the actinides remains one of the foremost challenges in all of quantum theory. In this proposal, we seek to combine previously independent actinide research on Brown’s campus into one directed effort aimed at elucidating the energetics and structure of uranium complexes. As part of this effort, we will develop and refine two new computational/theoretical tools - a hybrid DFT/impurity model method and a relativistic Auxiliary Field Quantum Monte Carlo - and test the energetic predictions of these techniques against cutting-edge Electrospray Ionization Photoelectron Spectroscopy (ESI-PES) experiments. The computational/theoretical tools to arise from this effort, which can handle both strong correlation and relativistic effects, will be among the most accurate available and furthermore will be able to scale up to larger problems such as the adsorption of actinides on colloidal surfaces. ESI-PES is moveover capable of sequentially building up a complex from its constituent ligands, giving researchers unprecedented access to complicated energetics one ligand at a time. By supporting this work, Brown will be fostering a mini-center among the actinide experts on campus that will place Brown researchers in a strong position to apply for center funding in the future.
PI: Brenda Rubenstein, Assistant Professor of Chemistry
Co-PIs: John Bradley Marston, Professor of Physics; Lai-Sheng Wang, Jesse H. and Louisa D. Sharp Metcalf Professor of Chemistry
Biological and Life Sciences
Toward a unified model of spatiotemporal coding in the spine-brain continuum*
Chronic pain affects ~7% of the U.S. population, fueling an opioid epidemic in the face of suboptimal therapies and lack of objective diagnostics. Here, we focus on a non-opioid neuromodulation-based therapy for the management of intractable pain, for example spinal cord stimulation (SCS). Our longterm five-year plan is to enhance our understanding of the basic mechanisms and pathways mediating pain transmission in the central nervous system as gateway for designing more effective neuromodulation therapies. In this application, we propose a one-year plan to conduct feasibility studies in support of our longterm project. Specific aims herein describe experiments: 1) to record neural data from spinal cord and brain structures specialized in the processing of pain signals in awake rodent models; and 2) to develop and validate a computational model of sensory processing in the spine-brain continuum towards testing novel therapies. Results obtained from these experiments will provide necessary preliminary data that would be critical for our team to compete for outside funding. Thus, this application details a carefully constructed plan for research synergy between two labs with overlapping research interests and complementary expertise. It is also a logical continuation of recently published data, patents and partnerships of both labs with government agencies and biotech companies. We believe the results from this study will provide a strong foundation for external, more sustainable research support.
PI: David Borton, Assistant Professor of Engineering
Co-PI: Carl Saab, Associate Professor of Neurosurgery (Research), Associate Professor of Neuroscience (Research)
*Multidisciplinary Research Seed Award for a team of two or more PI’s from distinctly different disciplines who are initiating a new collaboration with the goal to establish an ongoing, long-term connection across disciplines that is expected to lead to substantial external research funding through multi-investigator or center types of grants.
Biological and Life Sciences
Inhibiting T. brucei polo-like kinase as a novel approach for treating sleeping sickness
Trypansoma brucei is the causative agent of Human African Trypanosomiasis (HAT), also known as sleeping sickness, and nagana in cattle. These diseases cause extraordinary suffering in Sub-Saharan Africa, leading to many deaths and profound economic hardship. The few drugs available for treating HAT are extremely toxic and resistance to many of them has appeared in the field. Identifying cellular processes that can be targeted for drug discovery, ideally ones that are both unique to the parasite (to limit any detrimental effect on the mammalian host) and critical for its survival (so that its inhibition will kill or render the parasite incapable of dividing) is essential to spur the design of new therapeutics for treating HAT. We have recently demonstrated that the polo-like kinase homolog in T. brucei (TbPLK), and its substrates TbCentrin2 and TOEFAZ1 are essential for T. brucei cell division. Here we will use multiple approaches -- biochemistry, biophysics, cell biology and medicinal chemistry in order to elucidate the molecular basis of the TbPLK-substrate interaction and to identify novel inhibitors that block the interaction of TbPLK with its substrates.
PI: Christopher de Graffenried, Assistant Professor, Molecular Microbiology and Immunology
Co-PI: Rebecca Page, Professor, Molecular Biology, Cell Biology and Biochemistry; Michael Pollastri, Department of Chemistry and Chemical Biology, Northeastern University
Visualizing the dynamic architecture of germ granules
How do eukaryotic cells dynamically and spatially regulate gene expression during embryonic development, neural function, and cellular stress? Recently, breakthrough studies have identified micron sized granule structures composed of protein and mRNA as liquid-like physiological RNA processing and localization centers that are disrupted in disease. Unlike much of the complex machinery performing essential cell functions, there is poor understanding of the mechanistic function of the assemblies because no structural information is available on either the components or their interactions within these granules. The assembled team will directly address this critical gap in knowledge by applying complementary and collaborative structure/function experiments on the disordered protein:protein interaction domains that invariably are found in granule nucleating proteins. The proposed project will 1) test the functional significance of these “sticky” regions on granule localization and assembly within Xenopus laevis oocytes and 2) determine the atomic structure and intermolecular contacts of these regions both in vitro and in vivo. This project combines the strengths and recent successes of the laboratories uniquely suited to the goals. The project will use in vivo fluorescence imaging and in cell NMR approaches to map the specific contributions of structurally disordered domains to interactions that undergird granule assembly. The long-term goals of these studies will be to determine the molecular mechanisms of granule formation and RNA transport.
PI: Nicolas Fawzi, Assistant Professor, Molecular Pharmacology, Physiology and Biotechnology
Co-PI: Kimberly Mowry, Professor and Chair, Molecular Biology, Cell Biology and Biochemistry
Probing nutrient cycling in re-growing tropical forests to gain insights into local, regional and global biogeochemical cycles
Over 50% of tropical rainforests are re-growing from recent abandonment of grazing or agricultural land. These land uses typically deplete soil fertility, particularly nitrogen availability, which can constrain forest regrowth. In the coming decades, secondary tropical forests will play a critical role in absorbing carbon dioxide from the atmosphere, providing habitat for myriad species, and food, fuel and fiber to millions of people. We seek funds to gather preliminary data on nitrogen cycling in perhaps the least studied - and most threatened - tropical forest biome on Earth: The Atlantic Forest of Brazil. This ancient forest, as diverse as the Amazon, once stretched over 1,500 km along the east coast of Brazil, but is now 85% deforested. Its remnants house some of the highest levels of biodiversity on earth and there is increasing interest in its restoration. In order to understand how, where, and why secondary forests regrow (both planted and natural regeneration), we propose a series of experiments in a sequence of secondary forest sites that differ in age. Our data will add substantially to our understanding of secondary tropical forest nutrient cycling, and will inform restoration by focusing on a key group of organisms that are critical to the restoration of these forests - nitrogen-fixing trees. This work will provide training for postdoctoral research scholar, produce data that will be used in at least one grant proposal submission (to the National Science Foundation), and provide enough data for two high impact peer-reviewed publications.
PI: Stephen Porder, Associate Professor, Ecology and Evolutionary Biology and Environment and Society
Co-PI: Meredith Hastings, Associate Professor, Environment and Society and Earth, Environmental and Planetary Sciences
Drosophila as a translational model to study renal fibrosis
Renal fibrosis is a feature of chronic kidney disease that contributes to proteinuria, hypertension and renal failure. Many factors precipitate renal fibrosis including infection, osmotic stress, kidney injury and hormones. In particular, the steroid hormone aldosterone plays a role in fibrosis, but the mechanisms by which it does so, and how initial kidney injury induces its pathogenic effects are open, pressing problems. Accordingly, we anticipate a forthcoming NIH initiative to request animal (non-mouse) models of renal fibrosis. Toward this end we are working with the Drosophila Malpighian (renal) tubule system and have found that steroid hormones, including mammalian aldosterone and insect ecdysone, induce excess extracellular deposition of collagen IV (pericardin) at renal tubules and podocytes. Consistent with the pathology of renal fibrosis, mammalian aldosterone given to Drosophila reduces renal and cardiac function. To prepare for the anticipated NIH Request for Applications of renal disease models we aim to 1) Determine if aldosterone/ecdysone uses G-protein coupled receptor dopEcR (human GPER) signaling to regulate pericardin (collagen IV), 2) Establish proof of concept for drugs to moderate fly-modeled renal fibrosis, 3) Establish that fly kidney injury initiates renal fibrosis via aldosterone/ecdysone. Together these studies would position our Drosophila model and research team at Brown University to study underlying mechanisms of renal fibrosis, establish its potential as a tool to discover kidney disease therapy, and compete for a targeted funding opportunity.
PI: Marc Tatar, Professor, Ecology and Evolutionary Biology
Co-PI: Rujun Gong, Associate Professor (Research), Medicine
Developing a novel, high-throughput platform to study enzyme promiscuity
Enzymes are proteins that catalyze specific biochemical reactions. It is increasingly appreciated that in addition to their primary functions, many if not most enzymes have the capacity to also catalyze secondary reactions. However, the evolutionary role of such promiscuous enzymatic activities is poorly understood. We have developed a new research program to study the evolutionary implications of enzyme promiscuity, using the KpnI restriction enzyme as our model system. This enzyme cleaves DNA at a specific DNA recognition sequence, and defends the bacterium K. pneumonia against bacteria-specific viral pathogens called bacteriophage. OVPR Seed funding will support the development of a high-throughput experimental platform to quantify promiscuity in this system. Our approach subjects a large panel of KpnI variants to selection for their primary and promiscuous activities, and uses deep sequencing to quantify the resulting change in frequency of each variant. The project will generate a comprehensive map between all single amino acid mutations in KpnI and their effects on both primary and promiscuous KpnI activities. The results will constitute critical preliminary data for an R01 proposal investigating selection on promiscuity and its role in evolution, to be submitted to NIGMS in collaboration between labs in the EEB and MMI departments. The experimental platform developed in this proposal will be generalizable to large-scale investigation of mutational consequences in other enzymes, and will thus produce critical experimental and computational expertise to conduct such experiments at Brown.
PI: Daniel Weinreich, Associate Professor, Ecology and Evolutionary Biology
Co-PI: Richard Bennett, Professor, Molecular Microbiology and Immunology
Retail Environmental Change to Encourage Healthy Eating among Southeast Asian (SEA) Families: Leveraging Multi-Sector Partnerships with Asian Markets, Community Organizations and SEA Families
Overweight and obesity are poorly understood among Asian children. The limited available evidence suggests that Southeast Asian (SEA) children (specifically Hmong, Cambodian and Laotian) experience higher rates of obesity and related comorbidities than other Asian subgroups and whites, that disparities begin in early childhood, and that SEA are more similar to Latinos and African Americans with respect to overweight/obesity rates and obesity-related comorbidities. These data indicate that intervention during childhood and early adolescence (7-12 years) is warranted. Our multidisciplinary team that includes investigators and local community organizations is uniquely positioned to develop such an intervention to address the nutrition and physical activity needs of SEA families. Our overall is to address the current gaps in obesity prevention research by: 1) Conducting formative research with food retailers, SEA parents, grandparents, and children to inform development of a multi-level healthy eating intervention that will combine a retail healthy eating marketing campaign and financial incentives with a family based nutrition education intervention and; 2) Implementing the open pilot study to evaluate feasibility, acceptability and the preliminary efficacy of the intervention and to inform the design and implementation of a future RCT. We will use these data in an intervention mapping approach to plan a future NIH R01 submission. This research will position Brown at the forefront of obesity research with unique expertise in multi-level obesity prevention with SEA, a high priority, but extremely underserved group. This national reputation will be cemented further as Asians are the fasting growing racial group in the US.
PI: Akilah Dulin Keita, Assistant Professor, Behavioral and Social Sciences
Co-PI(s): Kim Gans, Professor, Department of Human Health and Family Studies, University of Connecticut; Alison Tovar, Assistant Professor, Department of Nutrition and Food Sciences, University of Rhode Island
Collaborators: Amy Nunn, Associate Professor, Behavioral and Social Sciences and Executive Director, Rhode Island Public Health Institute; Gemma Gorham, Project Director, Rhode Island Public Health Institute; Channavy Chhay, Executive Director, Center for Southeast Asians
Optimizing HIV pre-exposure prophylaxis (PrEP) uptake & adherence among stimulant using MSM
Men who have sex with men (MSM) are at elevated risk of HIV acquisition in US, and the number of new HIV diagnoses among this group is increasing annually. Similar trends have been seen in Rhode Island, with nearly 60% of incidence infections occurring among MSM. Problematic stimulant (crystal methamphetamine, cocaine and crack) use is a prevalent (20-times that of the general-population) and treatment-refractory problem in MSM, and highly predictive of HIV acquisition via an increased number of male sexual partners and frequent, prolonged, condomless sex. Several RCTs and demonstration projects provide strong evidence for the efficacy of a once-daily oral pill (emtricitabine/tenofovir) as pre-exposure prophylaxis (PrEP) for the prevention of HIV among uninfected, at-risk individuals, including MSM. The efficacy of PrEP is highly dependent on excellent adherence. Preliminary studies from our group document that MSM with stimulant use disorder are very interested in using PrEP (>90%), but their greatest reported-concern is that their drug use would lead to suboptimal adherence. Overview/Next-Steps: Providence is primed to be a site for developing and pilot-testing a PrEP adherence intervention for MSM with stimulant use disorder, with one of the first clinical PrEP programs in the country, led by our team at Miriam Hospital/Brown University. Informed by over a decade of formative research and addiction treatment experience with stimulant-abusing MSM, our interdisciplinary investigator team designed the "Pepped on PrEP" package - a counseling and problem-solving PrEP adherence intervention that addresses stimulant-abuse, and associated factors, as barriers to optimal adherence. We propose a pilot-RCT to assess the feasibility/acceptability of the "Pepped on PrEP" package, laying the groundwork for the next step of intervention development/testing--an NIH R01 efficacy trial.
PI: Matthew Mimiaga, Professor, Behavioral & Social Health Sciences, Epidemiology, and Psychiatry & Human Behavior
Co-Is: Philip Chan, Assistant Professor of Medicine; Kenneth Mayer, Professor of Medicine, Harvard Medical School; Adjunct Professor of Epidemiology and Medicine, Brown University
Development of on-site helium liquefaction for study of physical property of advanced materials and enabling novel applications
This Seed award will help with installation of a helium liquefier system. The liquefier is essential to provide a reliable and inexpensive supply of liquid helium, indispensable for achieving low temperature environment in which quantum effects can be studied and exploited to develop truly novel devices and sensors. Specifically, the proposed research focuses on investigation of emergent quantum properties in advanced materials and in quantum fluids; and, on development of high frequency transport measurements, high frequency devices, and sensors for astrophysical applications. Currently, due to the extremely high cost of liquid helium, a small part of this research is carried out at the National user facilities where very limited time is available for the experiments. Working at external facilities extremely limits our scientific productivity and creativity, i.e. ability to collect preliminary data. Thus, the most important aspect of helium availability is that it will allow us to collect preliminary data on many novel projects at nearly no cost. The ultimate results of this initial effort are development of unique, cutting-edge experimental capabilities and formation of competitive collaborative teams that will revolutionize the physical sciences at Brown. In addition, our efforts will open up new research opportunities for Brown’s materials and devices research programs, and will allow us to seek numerous new funding opportunities. With access to essentially cost free liquid helium, the investigators will be able to perform world-class leading research that is currently impossible to conduct at Brown due to the excessive cost and lack of reliable supply of helium.
PI: Vesna Mitrovic, Associate Professor, Physics
Co-PIs: Jim Valles, Professor, Physics; Humphrey J. Maris, Professor, Physics; Gregory Tucker, Professor, Physics;Alexander Zaslavsky, Professor, Engineering and Physics
Engaging the Chinese Lunar Exploration Program (CLEP): A Short-Term Investment with Long-Term Payoffs for Brown University
Faculty, students and staff from Brown University have historically been intimately involved in robotic and human Solar System exploration through active participation in experiments and space missions flown by the United States, the Soviet Union, Russia, the European Space Agency, India, and Japan. In the last decade, the People’s Republic of China has emerged as a major power in space exploration, launching astronauts into Earth orbit, building an Earth-orbiting space station and sending several very successful robotic missions to the Moon, with the ultimate goal of human lunar landings in the 2030s. U.S. Government guidelines have inhibited detailed NASA interactions with China but this attitude is changing rapidly as policy-makers seek ways for peaceful engagement. This period of transition represents a major opportunity for Planetary Geoscientists at Brown University. Here we describe a series of steps in the coming year that will position Brown University for future NASA funding for foundational engagement in the Chinese Lunar Exploration Program (CLEP) for the next two decades. These steps, based on our very successful 40+ year engagement with the Soviet Union/Russia, are four-fold: 1) Establish individual contacts with the key scientific personnel in the Chinese Lunar Exploration Program, 2) Outline a scientific strategy and plan of mutual interest, 3) Prepare robotic and human landing site selection and operations strategy documents that would form the core of the interactions, 4) Provide a sound and concrete basis for future proposals to NASA and the Chinese government for engagement in the Chinese Lunar Exploration Program.
PI: James Head, Professor, Earth, Environmental and Planetary Sciences
Prospective Brown-NUWC Collaboration to Develop New Sensor Materials for Underwater Acoustic Sensing
This Seed award supports novel research on materials never before used for flexible pressure and acoustic sensing, for which we plan to seek for external funding in partnership with the Naval Undersea Warfare Center (NUWC) at Newport, RI. While the PI's group is a recognized leader in nano-engineered new materials, its past experience and existing experimental capabilities have been on the mm to nm scale, much smaller than the scale, m to cm, needed by NUWC for applications in undersea sensing. To bridge this gap, we propose a pilot effort to scale up our fabrication and opto-acoustic characterization capabilities, by 10x, to the cm scale to prove the feasibility of scaling the base process while still leaving the more costly larger scale engineering-implementation to the better equipped and financed hands at NUWC. The proposed tasks for the collaborative effort between NUWC and Brown, that is anticipated to follow the Pilot project, are outlined below along with a projected pilot project cost breakdowns for FY16. These technologies offer a means for the use of new sensing materials that are applied for underwater acoustic sensing in a hydrophone device. These technologies offer flexibility, tunability, optical clearity, and conformal advantages that can be tailored for a number of other advantageous undersea applications.
PI: Jingming (Jimmy) Xu, Professor, Engineering and Physics
Co-PIs: Naval Undersea Warfare Center
Humanities & Social Sciences
Mapping Violence: Visualizing Histories of Loss
This award will support the development of an interactive platform that recovers and makes visible lost and obscured histories of racial violence in Texas from 1900 to 1930. This project grew through collaboration between the primary investigator and the John Nicholas Brown Center for Public Humanities at Brown University. Mapping Violence will enrich current understandings of histories of racial violence in the humanities, offer a model for using digital technology to present findings in the humanities to wider publics, engage educators and wider publics with this under-explored historical topic, and help advance Brown's reputation as a leader in developing digital humanities projects. Mapping Violence addresses fundamental questions on the best practices for visually representing histories of racial violence to a broad audience. How does one map a history of loss? This interdisciplinary project is at the intersection of ongoing conversations in the fields of American Studies, US History, Ethnic Studies, Digital Humanities, and the Public Humanities that explore how best to narrate histories of racial violence in the United States. A Seed award will fund two advanced graduate student research assistants and two undergraduate research assistants to expand and prepare the project database for production. The research team will take one trip to Texas for archival research and develop curated content for the platform. The award will advance a future application for a National Endowment for the Humanities Digital Projects for the Public Production Grant.
PI: Martinez, Monica, Assistant Professor, American Studies
The Rise, Spread, and Consequences of the Common Core State Standards Initiative in the U.S. Education Sector
The Common Core State Standards Initiative, launched in 2008, marks an historic attempt to improve the quality of instruction in American public schools, to reduce inequality in instruction, and to bring coherence across states and systems of schooling. Our interdisciplinary, multi-institutional team from Brown University, the University of Michigan, and Stanford University will explore whether and how this landmark initiative is improving school system management, classroom instruction, and student achievement in diverse local settings; and if so, why. Over the course of our five year study, our team will assess the development and use of Common Core through panel surveys of nationally representative samples of teachers, ethnographic studies of classroom practice, comparative cases of school systems in four states, and large scale data analysis of the determinants of student achievement over time. Our research program will not only provide the leading assessment of this historic initiative, but it will also establish new theoretical terrain on mechanisms of standardization in fragmented policy domains, challenge long-standing conventions used to measure state capacity, and reveal whether and how the development and diffusion of educational standards bears on inequality in American education. Seed funds will support a preliminary nationally representative survey of teachers and to support early interviews in our four case study states to help us prepare for and justify our multi-million dollar five year study.
PI: Susan Moffitt, Assistant Professor, Political Science
Co-PIs/Collaborators: David K. Cohen, John Dewey Collegiate Professor Ford School of Public Policy, School of Education, University of Michigan; Brian Rowan, Burke A. Hinsdale Collegiate Professor, School of Education, Institute for Social Research, University of Michigan; Sean F. Reardon, Professor, School of Education, Stanford University
Metatranscriptomic analysis to profile oral microbiome responses to broad-spectrum antibiotics during treatment of community-acquired pneumonia
The spread of antibiotic resistance is jeopardizing the efficacy of currently available antibiotics. Further complicating antibiotic therapy is a new awareness that antibiotic toxicity in non-pathogenic members of the microbiome can lead to detrimental health outcomes. To formulate therapies that have fewer complications we need to understand how untargeted bacteria respond to treatment. Metatranscriptomic analysis can profile responses in these off target bacteria and identify which bacteria are directly impacted by broad-spectrum antibiotics. We hypothesize that the differential regulation of antibiotic tolerance and resistance mechanisms can be used as a fingerprint to identify members of the microbiome that are impacted by antibiotic treatment. By conducting a community wide transcriptomic analysis of microbial populations with and without antibiotic treatment we can link well-established antibiotic response mechanisms to treatment outcomes. The key strength of this approach is that it can test antimicrobial perturbations in situ. Our initial focus will be on the oral microbiome of community-acquired pneumonia patients undergoing antibiotic treatment at Rhode Island Hospital. For this Seed project we have assembled a team that is uniquely suited to undertake this work, combining expertise in clinical infectious disease with microbiology and bioinformatics. The preliminary data and expertise obtained as part of this project will be a critical seed for the development of further work and funding opportunities. Finally, by developing sequencing and computational pipelines this project will develop capacity at Brown to study microbial flora in the context of infectious disease.
PI: Peter Belenky, Assistant Professor, Molecular Microbiology and Immunology
Co-PI: Eleftherios Mylonakis, Professor, Medicine
Assembling Complete Genomes Through Early Access to Nanopore DNA Sequencing
Despite the declining cost and increasing volume of highthroughput gene sequencing, it is still difficult and expensive to sequence and assemble genomes. Recently, we won competitive access to the initial release of a new nanopore sequencing technology (MinION) that has the promise to costeffectively read ultralong DNA fragments. These longer fragments are critical to successfully assembling complete genomes from scratch, and individual reads could potentially capture entire chromosomes. Leveraging this early access, we will research both the DNA preparation methods and data analysis methods needed to realize this promise, with immediate applications to our existing genomics projects. This interdisciplinary research will draw on expertise in biochemistry, computation, and statistics to tackle three key challenges: preserving ultralong DNA sequences so that they can be sequenced in their entirety by nanopre devices,; characterizing the signal space of the nanopore device and devloping statistical methods that align and assemble these signals; and testing hybrid assembly methods that combine nanopore sequence data with other highthroughput sequence data to assemble larger metazoan genomes. The preliminary methods and data generated by this work will enable new proposals for external funding in our groups and respective departments and strengthen pending proposals. The new computational methods developed here could result in a patent for Brown. Moreover, this work will establish a new DNA sequencing resource at Brown that will complement the existing Genomics Core Facility, can be shared by other labs with similar genomics projects, and will lead to further collaborations and funding opportunities.
PI: Susan A. Gerbi, Professor, Molecular Biology, Cell Biology and Biochemistry
CoPIs: Mark Howison, Director of Data Science, Computing and Information Services
Charles Lawrence, Professor, Division of Applied Mathematics
Benjamin J. Raphael, Associate Professor, Computer Science
Tissue Engineering for Personalized Medicine – 3D Human iPSC-Neuronal Microtissues
Modern drug development requires drug discovery, testing, and validation. It is costly and inefficient, and after drugs are brought to market, many fail. The goal of this project is to develop three-dimensional (3D) microtissues composed of patient-specific neural cells, in order to develop patient-specific disease modeling, drug testing and personalized medicine. Advantages of this approach are clear. Safety and efficacy studies on human cells can increase the likelihood of success in drug targeting. 3D cultures replicate the in vivo environment better than two-dimensional (2D) cultures, and as such, will provide more authentic assays for testing. We focus on the nervous system because there is an unmet need for fully comprehending and developing truly successful therapeutics for neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. This interdisciplinary team brings to bear the approaches of stem cell technology, neuroscience, neurophysiology, and tissue engineering on these complex problems. They will generate patient-specific neurons from human induced pluripotent stem cells (hiPSCs), including those from patients with Christianson syndrome and from their unaffected siblings. These neurons will be placed into high-throughput 3D cultures. hiPSC-neurons’ abilities to express key characteristics of neurons, including synaptic connections, will be confirmed, and their response to various drugs and disease assays will be explored. At the conclusion of this study, we will have key data to secure external funding for large-scale studies in these critical fields of research, and we will advance Brown’s position in the cutting- edge areas of pharmacogenomics and personalized medicine.
PI: Diane Hoffman-Kim, Associate Professor, Molecular Pharmacology, Physiology, and Biotechnology
Co-Investigators: Julie Kauer, Professor, Molecular Pharmacology, Physiology, and Biotechnology
Eric Morrow, Assistant Professor, Molecular Biology, Cell Biology and Biochemistry; Psychiatry and Human Behavior
Climatic and Environmental Reconstruction Using Lipid Biomarkers in Ancient Bones: Applications in Archaeology, Paleoclimatology and Paleontology
This proposed research builds on a recent exciting discovery of Professor Huang’s research group that a key class of climate-sensitive bacterial lipid compounds, is abundantly and well preserved in ancient bones. Ample research in the past few years has demonstrated that the molecular distribution of these bacteria-derived compounds in the environment faithfully records temperature and, in relatively dry regions, precipitation. Our discovery opens up a promising new avenue to extract paleoclimatic and paleoenvironmental information directly from animal or human bone samples, eliminating the key problem in environmental archaeology and paleontology of correlating such evidence directly to find contexts. Using the seed funds from Brown, we intend to demonstrate the efficacy of the new approach by analyzing a critical set of recent to modern bone samples across major climatic and environmental gradients; perform initial laboratory experiments to determine the time required for signatures to be fully registered upon bone burial in soil at controlled temperatures; analyze bone samples from important archaeological time intervals to obtain proof-of-concept data. A successful initial study as we propose here, will generate critical data with a major interdisciplinary impact that enable rapid publication of these innovative and original research technologies; they will in turn also pave the way for large collaborative research proposals across several departments at Brown to the NSF and other agencies.
PI: Yongsong Huang, Professor, Earth, Environmental, and Planetary Sciences
Co-PIs: Peter van Dommelen, Professor, Joukowsky Institute for Archaeology and the Ancient World
Andrew Scherer, Assistant Professor, Anthropology
Kevin Smith, Deputy Director and Chief Curator, Haffenreffer Museum of Anthropology
Engineering Orthogonal Ribosomes to Study Ribosome Function
The ribosome is the macromolecular machine responsible for the translation of genetic information in all forms of life. Over half of all antibiotics target the ribosome, and many are thought to act by interfering with ribosome conformational transitions. Thus deciphering the dynamic nature of the ribosome is important both for achieving a deeper understanding of a fundamental aspect of biology and for the rational design of new antibiotics. In our research collaboration, we will combine genetics with X-ray crystallography to determine the structures of ribosomes frozen in intermediate states by mutations at key functional sites. However, because the ribosome is an essential cellular component, the most informative mutations are expected to be lethal. Here, we propose to develop an orthogonal ribosome system to study ribosomes with otherwise lethal mutations. We will construct bacterial strains in which a subset of ribosomes has been altered to only translate one or more orthogonal reporter messenger RNAs. This system enables the production of ribosomes that would otherwise be toxic for the organism. The presence of compatible orthogonal reporter mRNAs and the insertion of an affinity tag further enable functional characterization in vivo as well as biochemical and crystallographic studies of these orthogonal ribosomes. After completion of the proposed work, we will be in position to submit applications to fund the long-range goals of this research program, determining the structures of ribosomes with mutations affecting conformational dynamics.
PIs: Gerwald Jogl, Associate Professor, Molecular Biology, Cell Biology and Biochemistry
Steven Gregory, Associate Professor (Research), Department of Molecular Biology, Cell Biology and Biochemistry
Exploring Innovative Delivery Methods for Brief Alcohol Interventions: The Electronic Mobile Alcohol Interventionist (EMAI)
We seek to prototype and evaluate an Electronic Mobile Alcohol Interventionist (EMAI), a robotic system that interacts with college students and helps them consider decreasing unhealthy drinking behaviors. The work is motivated by existing studies that show that robotic systems engender greater compliance than their on-screen counterparts and, at the same time, greater cost-effectiveness than therapies that require face-to-face interactions with trained experts. As a pilot study, we hope to replicate these results in an important concrete therapeutic context, specifically alcohol intervention. If successful, the project will open up opportunities for the team to seek grants at the boundary between the behavioral sciences and robotics, where novel behavioral therapies are joined with powerful new autonomous decision making algorithms to help improve health in a cost-effective manner.
PI: Michael Littman, Professor, Computer Science
Co-PI: Christopher Kahler, Professor, Behavioral and Social Sciences
Engineering Cell Morphology and Phenotype using Bioinspired Graphene Nanoarchitectures
Interactions between mammalian cells and nanoscale topographies represent an important but poorly understood signaling modality. In particular, the extracellular matrix (ECM) presents nanoscale architectural features that can direct cellular form and function, particularly during epithelial tissue remodeling and macrophage inflammatory responses. Remarkably, modern nanofabrication techniques enable artificial structures with sizes and geometries comparable to those found in the ECM. Here, we propose to explore the role of topographically patterned graphene oxide on cell morphology and phenotype. We will apply thin, stiff graphene oxide sheets to softer elastomeric substrates to generate periodic wrinkling patterns. We hypothesize that anisotropic geometries lead to the alignment and elongation of epithelial cells and macrophages. These biased nanoarchitectural cues may then alter gene expression to perturb cellular phenotype. We envision that this project will inspire new directions in nanomechanics with applications in stretchable electronics, energy storage and functional coatings. Moreover, this project will lead to new fundamental insights into how cell behaviors are modulated during embryonic development, wound healing, inflammation and cancer, with applications in designer biomaterials and regenerative medicine.
PI: Ian Y. Wong, Assistant Professor, School of Engineering; Molecular Pharmacology, Physiology and Biotechnology
Co-PIs: Agnes B. Kane, Professor, Pathology and Laboratory Medicine
Robert H. Hurt, Professor, School of Engineering
Nanoimprinted Nanowire Solar Cells
The eventual long-term goal of this research program is to create a cost-effective high-density nanowire (NW) solar cell that will exceed the so-called Shockley-Queisser power efficiency limit of ~29% for single-junction, single-crystalline silicon solar cells. The nanowire platform makes it possible to create multi-junction solar cells involving multiple materials that absorb more of the solar spectrum over a far smaller vertical cell thickness, resulting in lighter, more efficient cells. While both NWs and NW arrays have demonstrated impressive performance in the laboratory recently, cost-effective heteronanowire integration remains to be demonstrated. We have recently combined nanoimprint lithography, which permits effective fabrication of high-density (~500 nm pitch) arrays, with epitaxy (at NIST) of < 200 nm diameter Si nanowires to fabricate high-density solar cell arrays with improved efficiency over lower-density arrays grown from the usual vapor-liquid-solid (VLS) method using randomly dispersed metal seeds. Our three-dimensional finite-difference time-domain simulations show that due to diffractive scattering and light trapping, an array with 250 nm pitch should significantly outperform a blanket Si film of the same thickness – a result we plan to demonstrate experimentally during the next 6–9 months. At the same time, the small diameter of our NWs permits the combination of lattice-mismatched Ge/Si NW sections – an enabling technology for tandem Ge/Si NW solar cells combining reduced reflection with better solar spectrum coverage. The seed grant will strengthen the existing collaboration between the PIs and a National Laboratory, positioning the Brown-led team for success in extramural funding.
PI: Alexander Zaslavsky, Professor, School of Engineering; Physics
Co-PI: Domenico Pacifici, Assistant Professor, School of Engineering
Asia-Pacific in the Making of the Americas: Resources for Study
Begun three years ago by a group of Brown faculty and fellows working at the John Carter Brown Library (JCBL), the “Asia‐Pacific in the Making of the Americas: Toward a Global History” project has held six interdisciplinary, international symposia focused on transpacific interactions 1500‐1900. This Seed award will move the project to the next phase, to solidify the cohort of participating scholars through a digital publication and archive on the Brown Digital Repository. An ongoing collaboration will be established among Brown’s departments of History, English, American Studies, the Brown University Libraries and the JCBL to produce a digital multi‐authored publication that includes an archive of primary resources. This work entails close collaboration with librarians in the Center for Digital Scholarship and the JCBL. The Seed team will design and build the website using primary resources in the Brown Libraries and contributed essays, and will forge agreements with international institutional partners to add new materials to the site in the future.
PI: Evelyn Hu-DeHart, Professor, History & American Studies
Co-PIs: Caroline Frank, Visiting Assistant Professor, American Studies
Jim Egan, Professor, English
Librarians: Andy Ashton, Associate University Librarian for Digital Technologies
Elli Mylonas, Senior Digital Humanities Librarian
Jean Bauer, Digital Humanities Librarian
Rhode Island Child Obesogen Study-Pilot Phase*
Childhood obesity is the greatest public health threat to the current generation of United States children, and the identification of modifiable risk factors to prevent this epidemic is urgently needed. Prenatal insults may increase the risk of obesity by disrupting hormonally controlled mechanisms including adipogenesis, appetite, or epigenetics. Endocrine disrupting chemicals are a class of potential ‘obesogens’ that perturb these mechanisms and may increase the risk of obesity and cardiometabolic disorders. This project will build on the research infrastructure at Women and Infants Hospital Primary Care Center to conduct a pilot study and enroll 100 pregnant women at their first prenatal care clinic visit, and follow them and their offspring until delivery. Prenatal exposure to suspected contemporary endocrine disrupting obesogens will be measured. In addition, this study will measure biological intermediates involved in the development of obesity that are susceptible to endocrine disruption and associated with newborn adiposity. To ensure the associations between chemical obesogens and infant adiposity are independent of other important prenatal determinants of childhood obesity, this study will assess maternal diet, physical activity, psychosocial status, neighborhood level factors, and socioeconomic position. This cohort will serve as a resource to other Brown investigators interested in studying prenatal determinants of child and adult health.
Co-PIs: Joseph Braun, Assistant Professor, Epidemiology
Erika Werner, Assistant Professor, Obstetrics and Gynecology
Co-Investigators: Nicola Hawley, Research Fellow in Clinical Psychology
Karl Kelsey, Professor, Epidemiology & Pathology and Laboratory Medicine
Stephen McGarvey, Professor, Epidemiology & Anthropology
Maureen Phipps, Professor, Epidemiology & Obstetrics and Gynecology
Megan Romano, Postdoctoral Research Associate, Center for Environmental Health and Technology
David Savitz, Professor, Epidemiology & Obstetrics and Gynecology
Empower, Nudge: Increasing Dual Protection among Young Women in South Africa*
The overarching goal of this project is to reduce unintended pregnancies and sexually transmitted infections among young South African women, aged 18-30, who are defined as high-risk for unintended pregnancy and HIV acquisition. The main hypothesis is that a simple delivery innovation, when combined with health promotion strategies derived from behavioral economics, will motivate women’s greater uptake of effective contraception, and more consistent use over time. The specific objective is to test this hypothesis on a small-scale, in an urban setting in South Africa. This project will test a service delivery innovation, the “mini-packet,” and two kinds of innovative behavioral-economic incentives to promote initiation and adherence to voluntary contraception. A three-arm experiment in which the contraceptive packet alone will be compared against the contraceptive packet plus a loss-regret strategy (lottery), and the packet plus a standard (fixed) economic incentive will be piloted. A team of researchers from Brown and University of Cape Town (UCT) will deepen and extend cross-institution links though this multidisciplinary endeavor that incorporates distinct but overlapping research areas: behavioral and health economics, epidemiology, social and behavioral science, and behavior change.
PI: Omar Galárraga, Assistant Professor, Health Services Policy and Practice
Co-PI: Abigail Harrison, Assistant Professor (Research), Behavioral & Social Sciences
Co-Investigators: Mark Lurie, Assistant Professor, Epidemiology and Medicine
Kathleen Morrow, Associate Professor (Research), Psychiatry & Human Behavior and Behavioral and Social Sciences
Susan Short, Professor, Sociology
Brendan Maughan-Brown, Department of Economics, University of Cape Town
Scaling Evidence-Based Medicine via Automation and Crowdsourcing*
Evidence-Based Medicine (EBM) aspires to inform clinical care with all available evidence. The most important tool in the EBM arsenal is the systematic review, which provides an unbiased, comprehensive, (usually) quantitative summary of the evidence regarding a clinical question. Producing such reviews requires exhaustively identifying relevant articles and extracting from these the data to be synthesized. These tasks have become increasingly onerous as the biomedical literature base has exploded in recent years. This Seed team will capitalize on research strengths unique to Brown in big-data, crowdsourcing and EBM, and will represent the first effort to crowdsource systematic reviews. This project will investigate the application of novel technologies (crowdsourcing, automation and hybrid strategies combining them). This research thus has the potential to greatly optimize the conduct of systematic reviews. Moreover, the proposed approach of algorithmically combining domain expertise with low-cost human computation and automation to perform high-quality work at low cost is novel from a Computer Science perspective and will have wide application. This team will procure crowdsourced annotations for two systematic review tasks. This data will be used to assess the viability of crowdsourcing for systematic reviews, and to evaluate initial hybrid human/computer strategies.
PI: Byron Wallace, Assistant Professor (Research), Health Services, Policy & Practice
Co-PIs: Thomas Trikalinos, Associate Professor, Health Services, Policy & Practice
Tim Kraska, Assistant Professor, Computer Science
Ugur Cetintemel, Professor, Computer Science
Robot Telepresence in Improved Nursing Home Organization*
Robotics is poised to be a groundbreaking technology with the potential to drastically improve outcomes, increase access, and decrease costs for healthcare. The development of smart services to care for and engage our aging population is a critical need, especially the most vulnerable and expensive-to-care-for nursing home residents. While the benefits of robotic telepresence for individual older adults have been explored, it remains unclear how effective this technology will be when scaled to the level of a nursing home. Open empirical questions revolve around the level of acceptance of these systems by the residents, staff, and administrators of these facilities, as well as their feasibility within existing facility procedures. This pilot project will study the efficacy of networked robotic services in improving the processes and organization of nursing homes and the care of older adults. The Seed team will explore the effect of using commodity robot telepresence systems for more efficient and costeffective care through telemedicine. Resulting projects will address open questions along the social, empirical, computational, engineering, design, and cost-benefit dimensions of robot telepresence in nursing homes.
PI: Odest Chadwicke Jenkins, Associate Professor, Computer Science & Engineering
Co-PIs: Michael Littman, Professor, Computer Science
Richard Besdine, Professor, Medicine & Health Services, Policy and Practice
Terrie Fox Wetle, Dean, School of Public Health
Non-Invasive Measurement of Mechanical Properties of Biological Materials
Biomimetic research studies the underlying structure and function of biological materials in order to create better biologically inspired structural materials. Hierarchical structure lies at the core of the enhanced mechanical performance of biological materials such as the strength of seashells, the elasticity of spider silk, and the crack-resistance of biological sea sponge. This project seeks to understand the structure-function connection in some of nature's archetypal structural materials ultimately achieving complete understanding of the design principles underlying natural materials to make better, stronger, tougher materials. This team will collect preliminary data by investigating the mechanical properties of the basalia spicules in the marine sponge Euplectella Aspergillum using laser light scattering spectroscopy and correlating it with theoretical and computational modeling. This unique approach will provide noninvasive, spatially resolved measurements of the in situ mechanical properties of individual components in these hierarchical structures. This information will be used to create models to explain the enhanced properties of the composite. Having established the methods with sponge spicules, this team will be positioned to expand the scope of the project into other materials.
Co-PIs: Kristie Koski, Assistant Professor, Chemistry
Haneesh Kesari, Assistant Professor, Engineering
Blindfind: Empowering the Blind to Independently Navigate Public Indoor Environments*
The BlindFind system leverages the accelerating pace of discovery in computer vision and mobile computing power for the benefit of visually impaired citizens. The project will develop a working prototype of a wearable computer-vision system and complementary geo-location mapping data repository to assist the visually impaired as they navigate public indoor environments. The BlindFind system will consist of small cameras mounted on eyeglasses, a haptic belt, an Inertial Measurement Unit worn on the belt, and a bone-conduction headphone set – all connected to a small laptop carried in a backpack. A visually impaired user equipped with BlindFind will first pilot the system in a new building with sighted assistance. The user will document key points of interest and annotate a map of the space, while the system stores and overlays landmark information within a central repository of location-specific data. Future users of the system will benefit from the annotation and other stored data; they will be presented with verbal and haptic information to guide them when they interact with the system through an audio menu. The system will respond by issuing verbal guidance and navigation assistance as necessary.
PIs: Benjamin Kimia, Professor, Engineering
Pedro Felzenszwalb, Associate Professor, Engineering & Computer Science
Enabling Autonomous Flight of Drones in Complex, Unpredictable Environments*
Tropical forests are diverse, and much of this diversity is supported by the canopy. To better understand this diversity requires better characterization of the canopy, yet no present technology allows repeatable, direct, interactive observation within and around complex canopies. Unmanned aerial vehicles (UAVs), hold great promise, but there are formidable challenges to navigating UAVs in these complex environments. What is needed is sophisticated onboard processing that characterizes the environment in 3D and makes decisions in real time about its operation in order to achieve a given objective. Existing technology is far too costly and heavy for small aircraft, and the energy requirements do not allow the UAV to operate for more than a very short period of time. This project will develop new computing solutions for real-time navigation of UAVs in these complex environments. The challenge is to use a combination of software algorithm development, customized hardware design to accelerate these algorithms, and novel design space exploration techniques that produce solutions that carefully balance navigation accuracy, system energy consumption, and realtime response rate together. The results could be generalized beyond the tropical forest, wherever real time compute-intensive processing is needed in highly constrained environments.
PI: R. Iris Bahar, Professor, Engineering
Co-PIs: Sherief Reda, Associate Professor, Engineering
James Kellner, Assistant Professor, Ecology and Evolutionary Biology
Odest Chadwicke Jenkins, Associate Professor, Computer Science & Engineering
Genome-wide sequence analysis in severe autism and intellectual disability
Autism is a relatively common cognitive development disorder that is associated with profound costs for society and families. In particular, a cohort referred to as “difficult-to-treat autism” (DTT-Autism) shows no or minimal improvements in the context of current interventions. Recent progress in genetics has highlighted the role of rare and de novo genetic variation in the development of autism, pinpointing overall mutation burden as well as numerous heterogeneous and individually rare loci. The central hypothesis of this proposal is that DTT-Autism may be sub-divided into distinct sub-diagnoses based on whole-genome sequencing (WGS) and genetic network analysis. This proposal describes two main areas of investigation: (1) WGS will be performed, which we anticipate will uncover individual genetic causes relating to DTTAutism, including potentially treatable metabolic disorders. This will guide current use of WGS in autism diagnosis. (2) Novel algorithms emerging from this team will be applied to WGS data to identify challenging-to-find variants and genetic combinations associated with DTT-Autism. This project will result in the generation of a substantial volume of sequence data that will be made available to investigators within Brown University and at surrounding Rhode Island hospitals for analysis and application to their specific research interests.
PI: Eric Morrow, Assistant Professor, Molecular Biology, Cell Biology and Biochemistry & Psychiatry and Human Behavior
Co-PI: Sorin Istrail, Professor, Computer Science
Creating a Providence-based Working Group in Precision Medicine to Identify the Genetic Determinants of Marijuana Sensitivity
This pilot technology development project will create a precision medicine working group in Providence, Rhode Island and generate preliminary data for a multi-investigator grant submission to NIH. The precision medicine working group will be organized around the problem of discovering genetic modifiers and pathways that influence the complex set of physiological/behavioral responses to Tetrahydrocannabinol (THC). The strategy will be to apply novel genomic technologies for the simultaneous sequencing and screening of genomic variants in NIDA funded study participants. The working group will leverage existing clinical histories, patient panels, DNA storage arrangements, IRB approvals, and protocols for maintaining patient contact and confidentiality. This existing clinical infrastructure is complemented by functional and computational genomics expertise. Seed funds will catalyze the collaboration between the investigators by performing exome sequencing, annotation and functional data on each variant’s effect on gene processing to create the first individual(s) genome(s) that have been characterized at a functional level.
PI: Will Fairbrother, Associate Professor, Molecular Biology, Cell Biology & Biochemistry
Co-PIs: Valerie Knopik, Associate Professor (Research), Psychiatry and Human Behavior & Behavioral and Social Sciences
John McGeary, Assistant Professor, Psychiatry & Human Behavior
Ben Raphael, Associate Professor, Computer Science
Jane Metrik, Assistant Professor, Behavioral and Social Sciences (Research)
Multispectral Photoplethysmography for 3D Imaging and Quantitative Assessment of Blood Flow and Oxygen Content in Bone*
The long-term goal of this project is to develop optical techniques with which to characterize important physiologic parameters non-invasively by exploiting the interaction of light with human tissues. The specific aim is to develop a photon-based device with functional capabilities for real-time, non-invasive, quantitative measurement and, ultimately, 3D imaging of blood flow and oxygen content in bone. The proposed device will consist of a flexible, planar matrix of densely integrated light emitting diodes (LEDs) and photodetectors (PDs) used to map, non-invasively, the blood flow and oxygen content in bone. The proposed project will lead to a clinically relevant technology and associated device, namely a system for 3D Multispectral Photoplethysmography Imaging (3D-MPPGI), enabling the noninvasive, quantitative description of physiologic and pathophysiologic characteristics and facilitating the early diagnosis of diseases such as osteoarthritis (OA) among other diseases of bone. This program will place Brown at the forefront of this innovative technology by creating a device that would become the state-of-the-art for measurements of circulatory physiology in tissues and would have wide-ranging clinical relevance.
PI: Domenico Pacifici, Assistant Professor, School of Engineering
Co-PI: Roy Aaron, Professor, Orthopaedics & Molecular Pharmacology, Physiology, & Biotechnology
Using big data to crack the neural code*
The goal of this project is to understand how the cortex processes sensory information during natural everyday perception. Epileptic patients with implanted intracranial electrodes offer a unique opportunity to collect neural data at both a high temporal and spatial resolution. Currently terabytes of neural data from these patients are being left unexploited because of the lack of appropriate tools to relate neural activity to natural unconstrained real world events. This team has developed new automated techniques for discovering perceptual and cognitive states during natural every day vision, and proposes to build the largest existing neural database consisting of hours of brain activity while participants watch TV together with semantic annotations of the corresponding audio and visual content. The team will make this data available to the Brown community and organize a Neural Decoding Grand Challenge. This project will catalyze the formation of interdisciplinary research teams at the interface between big data, neuroscience and computer science and build on Brown’s existing strengths to establish the university as the leader in brain mapping and neural decoding.
Co-PIs: Thomas Serre, Assistant Professor, Cognitive, Linguistic & Psychological Sciences
Nicholas Stevenson Potter, Assistant Professor, Neurology & Neurosurgery
Establishing a technique for studying the neural circuits underlying alcohol responses in flies
Understanding how activation of neural circuits elicits distinct behaviors is a daunting challenge. The Seed team brings together a leading expert in modeling alcohol responses in flies and the developer of Tango-trace, a technique for tracing circuits in flies. This project will utilize fruit flies to gain insight into the mechanisms underlying their complex behavioral responses to alcohol that are remarkably similar to the responses of mammals. Flies are the ideal model for studying the neural circuits underlying these responses because of the availability of sophisticated genetic tools for manipulating specific neurons and the ability to perform genetic screens to identify genes involved in this process. This project will establish a configuration of Tango-Trace for tracing the circuits necessary for generating long-lasting memory of intoxication. Tracing these circuits is critical for understanding (1) whether memories for aversion and reward are formed and retrieved through distinct, nonoverlapping circuits, (2) how the memory of alcohol intoxication is acquired, consolidated, and retrieved, and (3) where the output response is initiated.
PI: Karla Kaun, Assistant Professor, Neuroscience
Co-PI: Gilad Barnea, Assistant Professor, Neuroscience
*Supported through funds dedicated to following up on outstanding projects proposed during the Signature Academic Initiative process.
Opening the Archives: Access to Information, Memory, and Justice Thirty Years After the End of the Brazilian Military Dictatorship
In 2012, Brazilian President Dilma Rousseff signed an Access to Information Law, establishing guidelines for declassifying documents and opening archives containing information about human rights violations committed by the Brazilian dictatorship (1964-85). She also appointed a Truth Commission to investigate the state’s involvement in torture and repression. Green has developed a joint project with a Brazilian historian to facilitate greater access to U.S. documents on Brazil for researchers in both countries. In conjunction with the Brazilian and U.S. National Archives, this collaborative team will coordinate a group of twelve Brown and two Brazilian students that will digitize and index U.S. State Department documents on Brazil from 1960 to 1980 that will appear on websites in Brazil and at Brown. The team will also identify documents for the Truth Commission’s investigations. This effort reinforces Brown’s reputation as the leading U.S. institution focusing on contemporary Brazilian history.
PI: James N. Green, Professor, History and Portuguese & Brazilian Studies
Co-PI: Sidnei Munhoz, State University of Maringá, Paraná Brazil
Solar Power by Optical Frequency Rectification with Plasmonic Concentrators Coupled to Junctions of Doped Mott Insulators
An alternative paradigm for the conversion of solar energy to electricity makes use of the collective electromagnetic nature of solar radiation instead of individual photons as conventional photovoltaic devices do. The electric field of sunlight is first intercepted by a nanoscale antenna, and then the oscillating electrical current is rectified into a useful DC current. Optical-frequency rectification – in effect a crystal radio that runs on visible light instead of radio waves – avoids altogether the mismatch between the photon energy and the semiconducting bandgap that limits the conversion efficiency of conventional photovoltaic cells. Solar rectification thus has the potential to create a cheaper and more efficient method for the exploitation of sunlight and could lead to a paradigm shift in solar technologies. This team will design and build prototype devices that combine plasmonic concentrators / antennas with novel rectifying junctions of doped Mott insulators to test the feasibility of the concept. A working device will be a compelling argument for external funding.
PI: Brad Marston, Professor, Physics
Co-PIs: Vladan Mlinar, Assistant Professor, Engineering (Research)
Domenico Pacifici, Assistant Professor, Engineering
Gang Xiao, Professor, Physics
Three-dimensional Traction Mapping Distinguish Neutrophils from Healthy and Septic Donors
Neutrophils are the most abundant white blood cell in the circulation and are among the first cells to response to an injury or infection; they are essential for health. Patients with decreased numbers of circulating neutrophils, or with inherited defects in neutrophil functions, are susceptible to opportunistic infections and have impaired wound healing. Efforts to study neutrophils under physiologically relevant settings have found that these cells are highly sensitive to physical and biochemical cues that regulate the magnitude of the cellular response to an insult. In order to translate laboratory findings to a better understanding of how the cells function in vivo, this Seed team will study neutrophils in a three dimensional setting rather than on standard 2D surfaces. This synergistic effort between laboratories in the Departments of Surgery at Rhode Island Hospital and the School Engineering will investigate neutrophil tractions in native 3D collagen gels and quantify cellular differences between healthy and septic cells.
PI: Christian Franck, Assistant Professor, Engineering
Co-PI: Jonathan Reichner, Associate Professor, Surgery (Research)
Phosphatase Inhibitor Design – A Unique Possibility for Brown University
The specific and reciprocal relationship between kinases and phosphatases controls most biological processes. Thus, when the balance is disrupted, the result is often disease. To date, efforts to modulate phosphate signaling to treat these diseases have focused on inhibiting kinases. However, it has recently become evident that the exquisite regulation of phosphorylation signaling is driven by tyrosine and serine/threonine phosphatases, rather than by kinases. Thus, one of the fastest growing areas of research is to identify potent, specific inhibitors of phosphatases. The Seed team will combine expertise in biochemistry, structural biology, biophysics and synthetic organic chemistry in order to develop novel, potent inhibitors of phosphatases. This project aims to develop novel peptomimetic inhibitors of the ser/thr phosphatase PP1 using data from multiple PP1 holoenzyme structures, molecularly characterize and optimize inhibitors that target the tyr phosphatase PTP1B, and develop new, potent immunosuppressant drugs using data from the ser/thr phosphatase calcineurin and chemical scaffolds already shown to target calcineurin.
PI: Wolfgang Peti, Associate Professor, Molecular Pharmacology, Physiology and Biotechnology)
Co-PIs: Christopher T. Seto, Associate Professor, Chemistry
Paul G. Williard, Professor, Chemistry
Making Sense of the Data Windfall: New Statistical Approaches to Evolutionary Analyses of Gene Expression
Many studies analyze gene expression to identify genes that play a functional role in particular biological processes. New tools make it possible to inexpensively measure the expression of all genes in a tissue sample. These tools, as applied in current study designs, are proving to be blunt instruments that turn up thousands of candidate genes for a particular biological process, most of which are erroneous by-catch. There is critical need to sharpen the focus of gene expression studies so that they identify a smaller set of more relevant genes. We propose to address this by adding an evolutionary dimension to gene expression studies. It will then be possible to identify speciﬁc genes that have evolutionary shifts in expression that are correlated with evolutionary changes in biological processes of interest. The hurdle to this approach is that statistical methods have not yet been developed, implemented, and tested for evolutionary analyses of high-throughput gene expression data. This project assembles an interdisciplinary team to do exactly this, and leverages Brown’s strong investments in genome sequencing and high performance computing.
PIs: Casey W. Dunn, Assistant Professor, Ecology and Evolutionary Biology
Xi Luo, Assistant Professor, Biostatistics
Zhijin Wu, Associate Professor, Biostatistics
The Role of Electrical Coupling Between Mitral Cells in Olfactory Coding*
Smell is the primary sense used by many animals to find food and mates and to avoid predators. Olfactory deficits in people are associated with loss of appetite, anhedonia and depression, and olfactory dysfunction can be an early sign of neurodegenerative diseases. The basic mechanisms by which the brain discriminates odors are obscure. Odors are detected by sensory neurons in the nose that project to special neurons called mitral cells. Patterns of mitral cell activity are transformed by the brain into the percept of a smell. Some mitral cells are electrically coupled through structures called gap junctions, also known as electrical synapses. This Seed team combines multidisciplinary expertise and the techniques of mouse genetics, electrophysiology, and behavioral analyses to study the role of electrical synapses in olfactory coding.
PI: Gilad Barnea, Assistant Professor, Neuroscience
Co-PI: Barry Connors, Chair and Professor, Neuroscience
The Role of the Right Hemisphere in Speech and Lexical Processing*
Past research using a variety of populations and research methodologies has produced conflicting findings on the role of the right hemisphere in speech and lexical (word) processing. This project research aims to examine this question by analyzing the effects of right hemisphere lesions on speech and lexical processing in the context of current models of the functional architecture of language using state-of-the-art behavioral paradigms, measures, and neuroimaging techniques. This novel approach will add to the continued and growing strength of the Brain Sciences at Brown by contributing to the breadth of approaches used and potentially opening new directions of research examining language functions of the right hemisphere using functional neuroimaging and the application of basic research findings (bench) to language rehabilitation (bedside). Additionally, it will add a new recruiting site at the Rhode Island Hospital.
PI: Sheila E. Blumstein, Professor, Cognitive Linguistic & Psychological Sciences
Co-PIs: Lynn Fanella, MRI Senior Research Technologist/Manager
Karen Furie, Chair and Professor, Neurology
Kathleen Kurowski, Assistant Professor, Cognitive Linguistic & Psychological Sciences (Research)
John Mertus, Assistant Professor, Cognitive Linguistic & Psychological Sciences (Research)
Carole Palumbo, Boston University School of Medicine and VA Boston Medical Center
Development of New Computational and Point of Care Platforms for HIV Drug Resistance**
HIV drug resistance is a major cause of treatment failure. The ability to identify drug resistance is important in patient care, and identification of specific drug resistance mutations can assist in efficient regimen design. Resistance testing, required in developed countries, is rarely used in resource-limited settings due to financial and infrastructure constraints. This is a major hurdle in the fight against HIV/AIDS since the vast majority of this pandemic is in resource limited settings. This project builds on preliminary research and a newly-developed microfluidic method termed SMART (Simple Method for Amplifying RNA Targets), to be integrated into a point of care chip platform, for drug resistance detection in resource limited settings. This Seed team will develop a computational platform for global analysis of position-specific pol sequence variation across geographic regions within HIV1 subtypes, develop a SMART Microfluidic Platform to amplify and detect drug resistance in a full-length HIV1 plasmid, and validate the platform in HIV-infected patient samples.
PI: Anubhav Tripathi, Associate Professor, Engineering
Co-PIs: Rami Kantor, Associate Professor, Medicine
Sorin Istrail, Professor, Computer Science
Joseph Hogan, Professor, Biostatistics
*Made possible through a generous donation of an anonymous donor
**Special Seed award for translational research
Climate Change, Biological Evolution, and Biogeochemical Cycles in Lakes of Central Sulawesi, Indonesia
The overarching goal of our research is to investigate coupled climatic, environmental, and biological evolution in central Indonesia over the last ~700,000 years. Indonesia lies at the heart of the Indo-Pacific Warm Pool, the largest pool of warm ocean water on Earth. Evaporation and rainfall over Indonesia controls the amount of water vapor in the Earth’s atmosphere and globally important climate processes such as the El Niño-Southern Oscillation. Long-term variations in Indonesian rainfall, combined with the tectonic evolution of the Indonesian archipelago, provide the environmental backdrop for the evolution of some of the most diverse ecosystems on Earth in Indonesia’s rainforests and lakes. We will investigate this variability by developing a Brown-led interdisciplinary science team to drill and analyze sediments from Lake Towuti, central Sulawesi, the largest lake in Indonesia.
PI: James Russell, Associate Professor, Department of Geological Sciences
Co-PIs: Anne Giblin, Senior Scientist, Marine Biological Laboratory at Woods Hole
Yongsong Huang, Associate Professor, Department of Geological Sciences
Stephen Parman, Assistant Professor, Department of Geological Sciences
Alberto Saal, Associate Professor, Department of Geological Sciences
Traffic Pollution and Acute Cardiovascular Events in Post-Menopausal Women
Cardiovascular disease is the leading cause of morbidity and mortality in the U.S. Wellenius will lead the first detailed study in a nationwide context of whether traffic pollution may increase the risk of cardiovascular events. This project will evaluate the association between long-term exposure to traffic pollution and cardiovascular risk within the Women’s Health Initiative (WHI), a large, national, prospective cohort study of 161,808 postmenopausal women. The proposed work is part of a broader research program to understand how different sources of ambient air pollution influence cardiovascular disease risk. The findings will likely have direct relevance on cardiovascular disease prevention by informing public health policy regarding the need for refinements to air pollution regulation, and position Brown University at the center of an exciting, important, and highly visible area of public health research.
PI: Gregory Wellenius, Assistant Professor, Department of Epidemiology
Co-PI: Charles Eaton, Professor, Departments of Family Medicine and Epidemiology
Eric A. Whitsel, Research Associate Professor, Department of Epidemiology, University of North Carolina Chapel Hill
Yi Wang, PhD, Post-Doctoral Research Associate, Department of Epidemiology
Melissa Eliot, PhD, Data Analyst/Programmer, Center for Environmental Health and Technology
Molecular and Cellular Mechanisms Underlying the Transition from Acute to Chronic Pain
Chronic pain is a serious health problem affecting millions of people in the USA alone. Chronic pain is highly prevalent in patients with diabetes, cancer, autoimmune deficiency, and following peripheral nerve injury. Strong evidence supports the theory that chronic pain is a maladaptive response of neurons to tissue injury or inflammation. The synapse is the site where neural transmission is scaled up and down in response to changes in neuronal input, but it is also now recognized as the critical pathological site in several brain diseases. Lipscombe and Kauer propose to begin to define fundamental cellular and molecular steps that support the development and maintenance of long-term changes in synaptic efficacy in the spinal dorsal horn, and then examine synaptic plasticity in the dorsal horn in animal models of chronic pain. The seed grant will allow them to garner preliminary data for future NIH applications.
PIs: Julie Kauer, Professor, Department of Molecular Pharmacology, Physiology, and Biotechnology
Diane Lipscombe, Professor, Department of Neuroscience
How Do Funding Mechanisms Affect Health Care Choices? Action for Health and Children’s Health in Mali
A key barrier to the cost-effective delivery of health care services in low-income countries is the lack of a full understanding of how families make decisions about when and where to seek healthcare. The aim of this project is to study these decisions in the context of children’s care. Sautmann and Dean will assess the relative importance of different factors that may affect the parents’ choice: financial constraints and costs; information and beliefs about the child’s need for care; and the preference of parents about trade-offs they must make e.g. between spending today and tomorrow, certain or uncertain outcomes or healthcare for their children versus other expenses. They frame their analysis in a dynamic model of healthcare decision-making, and use a randomized control trial of the “Action for Health” program of the Mali Health Organizing Project to estimate this model. The results will allow the researchers to predict changes in parents’ behavior and their impact on children’s health outcomes in response to different healthcare funding mechanisms.
PI: Anja Sautmann, Assistant Professor, Department of Economics
Co-PIs: Mark Dean, Assistant Professor, Department of Economics
Caitlin Cohen, M.D. Candidate, School of Medicine
The Impact of Agricultural Practices on Greenhouse Gas Emissions and Air Quality: A Case Study in New England
On a global basis, microbial activity in soils accounts for as much as 35% of nitrous oxide (N2O) emissions and nearly 20% of nitric oxide (NO) emissions. These trace gases are important in regulating Earth’s climate, while also influencing local air quality and acid rain deposition. Changes in N2O and NO emissions are anticipated with global changes in temperature, precipitation, and nitrogen fertilizer use, providing great potential for important feedbacks onto the climate and atmospheric systems. Hastings and Tang will develop a new system for automatically and simultaneously measuring the flux of N2O and NO from agricultural soils, and utilize this new technology in a pilot study to quantify the response functions of N2O and NO to parameters such as temperature, soil moisture, and nitrogen availability.
PIs: Meredith Hastings, Assistant Professor, Department of Geological Sciences and The Environmental change Initiative
Jianwu Tang, Assistant Scientist, Marine Biological Laboratory, the Ecosystems Center, and Brown Assistant Professor (MBL), Department of Geological Sciences.
Governance and Inequality in Indian Cities: A Seed Grant Proposal
Indian cities face tremendous challenges of governance because of entrenched inequalities and accelerating urban migration. Yet the social science literature on urban governance in India is conspicuous by its absence. This interdisciplinary team proposes to fill this gap through a long-term research project that is motivated by three fundamental questions. First, what are the predominant patterns of inequality in urban India and how is inequality structured? Second, how are Indian cities governed and how do these patterns of governance both reflect and impact patterns of inequality? Third, what forms of identity emerge in the migrant communities, as they come from villages to cities? And how do they view the state and fellow citizens? Who is us, who is them? This question, not often asked, is important for governance, for forms of consciousness have a relationship with what kinds of politics and political structures emerge, how political parties or civil society organizations mobilize citizens.
PI: Patrick Heller, Professor, Department of Sociology
Co PI: Ashutosh Varshney, Professor, Department of Political Science
Novel Micropatterned Culture Model for Developing New Therapeutic Strategies for Sudden Cardiac Death
Sudden cardiac death is a leading cause of death in industrialized countries. It is most commonly caused by ventricular fibrillation, a fatal heart rhythm disturbance (arrhythmia). Emerging evidence indicates an important genetic contribution to sudden cardiac death; however, the molecular determinants have remained elusive. This project aims to develop a highly innovative and translational culture model of human cardiac arrhythmia by patterning cardiomyocytes derived from neonatal transgenic rabbits carrying a human mutation causing long QT type 2 syndrome, a common genetic cause for sudden cardiac death. Hoffman-Kim, Mende, Koren and Choi will use this new culture model to investigate arrhythmia formation, the mechanisms underlying the protective effects of progesterone as well as identify progestin molecules ideally suitable to prevent cardiac arrhythmias and sudden cardiac death in long QT syndrome.
PI: Diane Hoffman-Kim, Associate Professor, Department of Molecular Pharmacology, Physiology and Biotechnology
Bum-Rak Choi, Assistant Professor, Department of Medicine, Rhode Island Hospital
Gideon Koren, Professor, Department of Medicine, Rhode Island Hospital
Ulrike Mende, Associate Professor, Department of medicine, Rhode Island Hospital
Genetic, Biochemical, and Bioinformatic Approaches to Understanding Microbial Degradation of Plant Biomass
The development of renewable energy sources, which can supplant fossil fuels, is of utmost importance. As replacements for fossil fuels, biofuels are helping to meet the growing global demands for energy. The proposed research project will establish a conceptual framework for genetically engineering microorganisms to produce biofuels from plant biomass, a renewable and readily available source of carbon. Inspiration for this strategy comes from the abilities soil-dwelling microorganisms to degrade and consume plant biomass. We have assembled a research team with complementary and appropriate expertise to mine and elucidate the metabolic pathways for plant biomass consumption in soil-dwelling Streptomyces bacteria. By necessity, the project involves the synergistic application of experimental methods from genetics, biochemistry, computational biology, and chemistry.
PI: Jason Sello, Associate Professor, Department of Chemistry
Co-PIs: Rebecca Page, Assistant Professor, Department of Molecular Biology, cell Biology and Biochemistry
Charles Lawrence, Professor, Department of Applied Mathematics