Brian Smith - US grants

This award provides funds to a group of neuroscientists at the University of Arizona for the purchase of a computer, networking hardware, and associated software. This equipment will be used to analyze experimental data resulting from comparative studies of olfaction and spatial orientation in lower and higher animals. Though collaborations with mathematicians, these investigators plan to generate models for nerve cell interactions that appear fundamental to these processes. Models will be based on anatomical and electrophysiological properties of the nervous system. Other models will have an explicitly behavioral basis. The models will developed using a neural network simulation program called GENESIS and the computer. Interspecific comparisons have traditionally provided a useful tool in understanding the underlying mechanisms of biological processes. Increasingly, the use of experimental data and theoretical schemes for the synthesis of models that make detailed predictions has played an equally important role in modern biology. Olfaction and spatial orientation are both problems of nervous integration that have interested neurobiologists for some time. The use of computational models, in particular neural network models, to get at the underlying integrative mechanisms is a promising approach to these classical problems.

flow cytometry; biomedical equipment resource; biomedical equipment purchase;

Cardiopulmonary bypass (CPB) is associated with clinically significant platelet dysfunction resulting in bleeding, and alterations in leukocyte and endothelial cell function resulting in pulmonary edema, immunodeficiency, and occasionally widespread end organ damage. The investigations proposed here are predicted on the hypothesis that these effects are interrelated, specifically by virtue of CPB induced dynamic alterations in the adhesive interactions of platelets (plts), leukocytes (WBC), and endothelial cells (EC). Preliminary data from our laboratory has demonstrated that (1) specific cell-cell adhesion receptors on plts are quantitatively and qualitatively altered in vivo by CPB, in particular the selectin GMP-140, the integrin gpIIb/IIIa, and the von Willebrand's Factor receptor gpIb; (2) specific receptors on neutrophils (PMN), monocytes, and lymphocytes are similarly altered including the LeuCAM integrin CD11b; (3) these changes result in a time-dependent predictable alteration in in vivo platelet-leukocyte binding during CPB and to other functional changes involved in homotypic and heterotypic cell interactions; and (4) endothelial cell derived endothelin increases in the plasma of patients on CBP and may alter GMP-140 expression on EC. Our laboratory has developed new in vivo techniques for the investigation of these phenomenon which because of their exceedingly low blood volume requirements are applicable to patients of all ages. These techniques include the use of flow cytometry for the study of non-adherent cells and newly available microscope based interactive laser cytometry for the investigation of endothelial cell, adherent phagocyte, and platelet biology. The five specific aims of this project are to address the questions: (1) what are the quantitative and qualitative changes in platelet adhesion receptors that occur during CPB?; (2) what are the changes in leukocyte adhesion receptors during CPB?; (3) what alterations occur in vivo in platelet- leukocyte binding during CPB and what are the functional consequences of this interaction?; (4) what are the effects of these platelet-WBC changes on endothelial cells and how do EC alter platelet-WBC interaction?; (5) do the alterations assessed above correlate with clinical outcome post CPB? The long term goal of the project is to use this knowledge to design therapeutic interventions to minimize the adverse consequences of CPB, especially in the young and the elderly.

9422146 Huttenlocher This award is to purchase equipment for support of research in Computer and Information Science and Engineering. Specifically, this award will be used for equipment to support several projects in the processing and analysis of digital video: 1) video motion analysis for annotation and browsing -- detecting significant changes in camera motion and tracking moving objects in order to automatically segment unstructured video; 2) adaptive video compression -- using motion segmentation in compression; 3) video transcoding; 4) network protocols for continuous media; and 5) compression-- tolerant image analysis -- including development of algorithms that operate directly on compressed video data. ***

Studies outlined below will investigate the quantitative and molecular genetic bases for variation in learning performance in the honey bee, Apis mellifera. Research into the bases of learning and memory in invertebrates such as mollusks and insects has demonstrated that fundamental properties of behavioral plasticity developed in studies of vertebrates apply across a broad phylogenetic spectrum. Yet, the genetic bases for learning traits are only beginning to be studied. Honey bees provide excellent opportunities for studying genetic factors that influence learning behavior because of the potential to apply several powerful behavioral paradigms for studying learning in vertebrates. The series of proposed studies will take advantage of the ability to train and analyze honey bee drones (males). Drones arise from unfertilized eggs and are thus haploid recombinants of the maternal genotype. Quantitative genetic selection on a haploid proceeds faster than it would on a diploid. Furthermore, linkage mapping from haploid genotypes using a map recently developed from a series of RAPD primers will not have the complications of such mapping using diploid genotypes. The specific aims of the studies are: * To further determine the quantitative genetic bases underlying variability in olfactory learning performance. Lines will be selected for fast versus slow reversal learning performance relative to unselected control lines. Use of this conditioning protocol and inclusion of appropriate control procedures will allow us to test whether associative learning performance can be selected without correlated responses in sensitization or motor systems. * To investigate the molecular genetic background using a linkage map established from RAPD genetic markers. These kinds of analyses will be carried out in recombinant F2 drone progeny of hybrid queens, in which spurious correlations due to founder effects in small base populations would be attenuated.

This award is made under the high performance connections portion of NCRI's "Connections to the Internet" announcement, NSF 96-64. It provides partial support for two years for a DS-3 connection to the vBNS. Applications include projects in computational biology, computational chemistry, materials science, distributed high performance computing, the Long Term Environmental Research (LTER) Program, and visual programming environments. Collaborating institutions include most of the Internet 2 institutions, as well as the Pittsburgh Supercomputing Center, National Center for Supercomputing Applications, and the National Center for Atmospheric Research.

This project will develop and test a portable, intermediate range, narrow band telemetry system electroencephalography (EEG) epilepsy monitoring and evaluations. This will allow round-the-clock epilepsy monitoring without having the subject tethered with wires and also enables the patients to be monitored ou the specialized hospital epilepsy monitoring units. The proposed EEG Epilepsy Telemetry system will have numerous advantages. Outpatient EEG epilepsy monitoring allows for prolonged monitoring of the patients in their home environment which eliminates the of over a week of hospitalization at the specialized epilepsy monitoring units. Extension of EEG recording ou the confines of the EEG laboratory on a routine basis allows physicians to take full advantage of the pote usefulness of continuous, long-term EEG monitoring. The increased amount of data which can be processed the patient's normal home environment serves to shorten hospitalization, decreases risk to the patient providing more accurate diagnostic information, increases the number of patients who can be accommodated at epilepsy centers, and decreases per-patient costs. This system is particularly convenient for pediatric pat because it minimizes the time away from home. Children, who usually do not understand the importance of diagnostic test, may be less patient in a restrictive and boring setting and are more likely to interfere with apparatus. PROPOSED COMMERCIAL APPLICATION: In addition to being used to monitor EEG for Epilepsy, the telemetry system can be used to communicate vital signs on patients in thee hospital or at home without interfering with similar systems of other patients. The same unit has numerous industrial and commercial applications for real time control and monitoring. The system can also be used for markets as diverse as conducting special studies in the workplace to control virtual reality games with brainwaves.

During collection and storage, platelets develop a variety of structural and in vitro functional abnormalities, including alterations in surface membrane constituents, granule release, signal transduction, membrane phospholipid composition, energy metabolism and cytoskeletal organization. The development of this platelet storage lesion is the result of platelet activation, opsonization, hypermetabolism and senescence. It is also known that upon transfusion some of these in vitro abnormalities reverse; however, the definition of which abnormalities are readily reversible and which are irreversible is not well understood. Based on preliminary data, we hypothesize that (a) abnormalities previously thought to be irreversible may not be so, for example, P-selectin expression on the platelet surface; (b) a significant portion of both the activation-derived and the opsonization- derived platelet lesion is secondary to complement activation during collection and storage; and (c) that a portion of the metabolic abnormalities observed are also directly linked to platelet activation via mitochondrial dysfunction induced by normal activation events. We have developed an in vitro whole blood model of transfusion that allows one to separately analyze subsets of "transfused" platelets simultaneously with native platelets. In addition, we have previously investigated in detail the participation of specific complement components in the development of the somewhat analogous platelet lesion which is associated with extracorporeal circulation and now have preliminary data to suggest similar complement participation in the storage lesion. We now propose to: (a) define which aspects of the platelet storage lesion are reversible upon reintroduction of the stored platelets into the normal whole blood milieu using the transfusion model; and (b) define the role of specific complement components in the generation of the activation, opsonization and metabolic storage lesion under different conditions of collection and storage. We will use specific blocking molecules, multiparameter flow cytometric and image analysis technology, cytoskeletal and signal transduction analysis and newly applied metabolic assays. The long term goal of the project, which combines the synergistic expertise of several established investigators, is to improve the clinical results of platelet transfusion.

DESCRIPTION: (Adapted from the investigator's abstract) Cardiopulmonary bypass profoundly alters the interacting coagulation and immune systems, resulting in seemingly contradictory coagulopathic, prothrombotic, immunosuppressive and proinflammatory diatheses that are responsible for cardiopulmonary bypass related pulmonary and myocardial injury and bleeding early during bypass and hypercoagulability and immunologic disturbances later in cardiopulmonary bypass. As demonstrated previously under this grant, cardiopulmonary bypass results in a dynamic alteration in platelet-leukocyte-erythrocyte-endothelial adhesive and functional interactions, in part initiated by terminal membrane component generation. Using in-vivo studies and in-vitro whole blood model and a simulated extracorporeal circulation model, the PI has shown that antigenic and functional upregulation of specific beta2 integrins occurs on circulating phagocytes in cardiopulmonary bypass, platelet alpha-granule release and P-selectin expression occurs with formation of circulating platelet -leukocyte conjugates during cardiopulmonary bypass at anti-complement C5 monoclonal antibody blocks both platelet and neutrophil activation during simulated extracorporeal circulation. Further work suggests that damaged and reticulated red blood cells promote activated platelet microparticle formation, that platelet activation may be a result of C5b-9 while adhesion molecule upregulation occurs a consequence of C5a activity. Furthermore, neutrophil granule release and adhesion upregulation are separable events and reticulated platelets represent a platelet subset which shows differential functional activity and may by preferentially lost during cardiopulmonary bypass. The aims of this application are to 1) define which complement components and other mediators initiate which parameters of platelet white blood cell endothelial activation 2) to define the molecular basis of erythrocyte-platelet-white blood cells interactions which generate cellular and soluble mediators of coagulation and inflammation in cardiopulmonary bypass and to define alterations in endothelial cells inducted by simulated extracorporeal circulation using an addition to the current model. The long term goals of these studies is to develop therapeutic strategies to alleviate complications of extracorporeal circulation and to understand the basic biology of platelet-white blood cell-erthyrocyte-endothelial interactions.

This project will develop an all purpose 8-channel miniature, intermediate range, wireless Bioelectric Monitor that can be marketed at under $5000.00. The device is extremely flexible such that the amplifier gains and filters can be adjusted using a WindowsTM-based operator interface software. This feature allows the device to be used for monitoring any type of bioelectric signals such as electroencephalogram (EEG), electromyogram (EMG), electrocardiogram (ECG), etc. The particular application of the device during this Phase II project will be in auditory evoked response (AER) evaluations of infants and toddlers. AER has been found to be the most accurate technique to predict at birth the language and cognitive skills that the infant will have three to five years later. The Bioelectric Monitor to be developed during this project will be tested for its functionality and robustness in AER evaluations of about 50 subjects (term infants and infants with Bronchopulmonary Dysplasia (BPD) and very low birth weight (VLBW)) at two separate clinical sites. The AER evaluations will be compared with the standard methods of cognitive assessments. PROPOSED COMMERCIAL APPLICATION: In addition to being used to monitor Bioelectric signals such as EEG and EMGs, the miniature, narrow band telemetry system can be used to communicate the vital signs on patients in the hospital or at home without interfering with similar systems of other patients. The same unit has numerous industrial and commercial applications for real time control and monitoring. Due to its low cost, it can also be used for control of multiple mobile robots and virtual reality games.

Brian L. Smith
University of Virginia
Department of Civil Engineering

Proposal Number 9984149


Time-Critical Applications of Nonparametric Regression: Harnessing the Power of Information Technology for Infrastructure Management Systems

As greater demands are placed on infrastructure systems, civil engineers are being called upon to develop management systems to enable the efficient use of infrastructure capacity. Advances in information technology allow infrastructure management systems to collect large quantities of data describing the state of the system. Currently, this data is used to develop management strategies that react to current conditions. However, it is desirable to develop proactive strategies based on forecasted demand for service. Nonparametric regression models have high potential to support demand forecasting. The premise of nonparametric regression is that by searching a database of past experiences, one can find cases that are similar to the current state of the system. Then, these past cases can be used to predict the future system state. Unfortunately, the complexity of searching a large database is so great that nonparametric regression may be unable to meet the time requirements of infrastructure management systems. The purpose of this effort is to address the search complexity of nonparametric regression, making it a viable tool for infrastructure management demand forecasting.

The research will focus on data management, data structure, and advanced computing approaches. Data management will be considered to attempt to intelligently prune records of the database without unacceptably degrading the accuracy of the model. Data structures will be investigated that will reduce search complexity through sorting/storing the data in innovative ways. Advanced computing technologies, particularly distributed computing, will also be explored.

The education effort will focus on preparing civil engineers to effectively apply information technology, a critical infrastructure management requirement. Materials will be developed to strengthen information technology education in the civil engineering curriculum, students will work on interdisciplinary teams, steps will be taken to attract and retain underrepresented groups, and web-based educational materials will be developed.

This research focuses on children's television and how it can be enhanced with digital technologies. We envision the convergence between television and computing leading to new types of learning interactions between children and parents around television content. In particular, we may be able to borrow features from educational reform movements to develop novel, informal learning around television. For instance, if we can model question-asking and inquiry strategies to parents and children, they may be able to adopt and use them to structure learning conversations in the home.

We add a new layer of digital information to the analog television experience, justification structures that explain how and why a television program is intended to facilitate learning. By providing additional meta-information about the educational intentions of a program, we hope to engage parents and children in critical reflection and inquiry around television content. The justification structures are digitial design rationales, capturing elements of the production process that would otherwise be hidden from viewers (e.g., historical justifications for the inclusion of content, alternative viewpoints and additional questions that were omitted from the final program).

To develop the justification structures, we will examine how television producers currently design and develop their programming. As we understand their practices and conceptions of learning, we will define justification structures that make explicit the tacit assumptions underlying their programming decisions. We will then design and deploy digital television technologies to families in low-income housing projects with the goals of:

o Developing a theory of justification that describes the content and rationale behind children's television programming

o Assessing the impact of justification structures on parent-child interactions and learning

o Rethinking the content of educational television in light of these justification structures

PROPOSAL SUMMARY This proposal is for renewal of our postdoctoral research training grant in Immunohematology and Transfusion Medicine that was initiated in 2001. The six position program provides a highly organized 2-3 year experience of focused dedicated didactics, seminars, and, most importantly, an intense research experience with one of 29 well-established, highly interactive, and well-funded cross-disciplinary mentors representing eight different primary departments. The goal is to generate productive MD and MD/PhD physician- scientists as well as PhD scientists and clinician-scientists, who will be launched on a lifelong investigative career pursuing basic, translational, and clinical research in this relatively underrepresented field. Careful career development by an individualized Training and Career Advisory Committee is a hallmark of the program. Two major degree- granting tracks are also available in addition to the core post-doctoral program: an Investigative Medicine PhD available to MD-only trainees who wish to obtain a more expansive research background mimicking that of an MD/PhD; and a Masters of Biomedical Engineering for trainees with a past basic biomedicine emphasis who wish to add a diagnostic and cellular therapeutic engineering dimension to their knowledge base. Drawn from an MD, MD/PhD, and PhD candidate pool focused on those whose background is Laboratory Medicine & Pathology (a pool which has always included at least 10 fold more excellent, training grant eligible, candidates than can be accepted into the T32 program), outcomes have been quite positive. Of the 21 graduates of the T32 program over 15 years, there was an average of 4.2 papers and 2.2 first-author papers per trainee published as a direct result of the T32 training and all 21 graduates have published papers in the last three years as a result of their continuing scientific careers. All are in scientific careers; 48% are in tenure-track research-intensive positions at research universities; 19% in careers on the ladder research track at major universities, and 21% are in senior scientist positions in industry. The core T32 is leveraged, that is, the entire enrollment in the Laboratory Medicine Departmental Immunohematology-Transfusion Medicine research training program is greater than the T32-funded individuals alone by about 50%, since the extended program includes individuals on other funding mechanisms sharing the same infrastructure. Including trainees in the extended program, there are 63% University tenure-track faculty, 13% University research track faculty, and 19% in senior scientist positions in industry. As the only benign hematology T32 at Yale, one of the few Immunohematology T32s in the country that emphasizes PhD clinician-scientists along with MD and MD/PhD physician-scientists, and also one of the few postdoctoral hematology T32s that includes bioengineering and PhD degree tracks, this program fills an important research training need both at Yale and nationally.

[unreadable] DESCRIPTION (provided by applicant): Adverse outcomes in cardiac surgery associated with cardiopulmonary bypass (CPB) include neurocognitive deficits, myocardial ischemia, peri-operative bleeding, and post-operative thrombosis. Our overall goal is to elucidate the underlying pathophysiology of CPB which involves activation of, and cross-talk between, cellular and soluble hemostatic and inflammatory systems, with the aim of devising therapeutic interventions. Our studies are based on both in vitro models and clinical material. Under the past aegis of this grant, we have helped define normal physiology of platelet-leukocyte interactions; shown that CPB results in upregulation of specific p 2 integrins on leukocytes, P-selectin on platelets, and formation of circulating leukocyte-platelet conjugates in vitro and in vivo; defined differential roles for specific complement and coagulation activation products in the induction of platelet versus neutrophil versus monocyte activation; shown that C5 complement blockade carried out in clinical CPB is associated with similar effects to those seen in vitro, and, in a pilot study, a reduction in CPB adverse outcomes; and discovered that the PL-A1/A2 genetic polymorphism of platelet gp llla is associated with different neurologic and myocardial outcomes in clinical CPB. Our new specific aims are: (la) using in vitro models, determine the role of the C5a and C3a receptors in neutrophil, monocyte and platelet activation induced by simulated extracorporeal circulation (SECC); since preliminary data suggests the unexpected finding that C5aR blockade abrogates platelet activation, determine the responsible mechanism; (1 b) determine the role of the lectin complement pathway in CPB by (i) correlating in vivo complement activation with interpatient genetic variability in mannose binding lectin (MBL) levels and acquired CRP levels, (ii) examining the role of MBL in SECC; (2a) determine differences in human monocyte subsets, defined by CD64/CD16/CD14 expression, with respect to p.2 in and tissue factor regulation; (2b) examine monocyte subset distribution during in vivo and in vitro CPB; using expression array technology, define the pattern of monocyte inflammatory gene expression induced by SECC; (3) examine the effects of SECC on human endothelial cells by in vitro modeling, specifically including alterations in tissue factor regulation and the effect of differential complement components

This project aims to understand the influence of social organization on epidemiology, using the honey bee colony as a model. It is based on the hypothesis that the social network within a large group, which is fundamental to its integration, also makes it relatively easy for pathogens to sweep across the entire group. Such high susceptibility of social groups to epidemics also makes it likely that the design of the social network is under strong selection pressure to evolve a structure that impedes the transmission of pathogens. There may be segregating forces within the network that reduce the velocity of pathogen transmission or the network could flexibly alter its structure as a defensive response against an invading pathogen.

Most of the current ideas in epidemiology are either theoretical or based on secondary data due to an obvious lack of experimental opportunities. The honey bee colony, with its highly complex social organization and a tremendous array of host-parasite interactions, provides a one-of-a-kind opportunity to further our understanding of epidemic phenomena. This bee colony is also highly amenable to experimental manipulations making it possible to study the treatment effects of numerous social and demographic variables on the spread of an epidemic. Such findings have enormous applications in designing disease prevention and control methods for any close-knit social group such as a crowded urban situation, especially given the current challenges posed by bioterrorism and emerging infectious diseases.

Abstract Not Provided.

ABSTRACT for CMS 0510404

The current transportation research environment uses sophisticated modeling of individual components of the surface transportation system to improve performance of the overall system. For example, route guidance models allow for the investigation of benefits (to the individual vehicle and the system) of information provision to drivers, while signal optimization programs determine near-optimal signal timing given traffic data. Traditionally, this breakdown of models into the vehicle and infrastructure domains has been appropriate in that there has been little or no dynamic interaction between the two systems. Signal control systems, for example, currently determine signal timing based on historical data or, in the best case, incorporate dynamic control that is driven by data from loop detectors or other fixed sensors. There is, however, no near real-time information available directly from the vehicles, such as speed, previous locations, vehicle origin and destination, and driver preferences. Vehicle route guidance systems also use historical and near real-time traffic data to assist drivers in route selection but typically do not explicitly consider the phasing of nearby signals. Given the current investigation of technical issues associated with vehicle-vehicle and vehicle-infrastructure communication (referred to as vehicle-infrastructure integration - VII), there is a need to critically examine how such an infrastructure could be used to improve surface transportation. This project proposes both development of modeling tools capable of capturing such networking and development of methods for beneficial integration. The fundamental basic questions that the investigator and his colleagues explore are, therefore, 1) What information should be provided?, 2) Who should receive information?, 3) When should the information be provided?, and 4) How will the information be used?

The automobile is the dominant mode of surface transportation in the United States. The surface transportation system that has developed to enable this mode of travel is made up of two components: (1) individual travelers in their automobiles (referred to as vehicles), and (2) the roadway/traffic control network (referred to as infrastructure). To date, these components are "managed" in an independent manner. Drivers make decisions with very little knowledge of the entire networks status, and infrastructure operators make decisions regarding network control (primarily through signal systems) based on vehicle count data collected at limited locations. This lack of "cooperation" between the components has evolved primarily due to the lack of affordable information technology that would allow the components to easily share data and make collective decisions that would benefit the entire system. Practical benefits of such cooperation include route guidance which assists drivers in minimizing time spent at red lights. It also includes traffic signal systems which can sense and respond quickly to reduce vehicle stops and delays. As wide-area wireless networks become commercially available, and in-vehicle computer systems become affordable and pervasive, the information technology will soon be available to radically rethink how the surface transportation infrastructure should be operated. Because of their mandate and economic interests, the vehicle industry concentrates on research and development to improve the vehicle component of the system - with little consideration of the infrastructure. Similarly, transportation agencies concentrate on research to improve the infrastructure - with little consideration of the vehicle component. Thus, the science base currently does not exist to allow industry and public officials to best direct this new system. The investigators are developing the science and model base for integrated/cooperative surface transportation system control and management made possible by advanced information technology. This will allow for the investigation of the integration of information technology and the transportation infrastructure, a critical step in the evolution of the US transportation system.

This project will research distributed, online fantasy basketball games, which are quite popular with many kinds of players, including informal science education under-represented groups, and which entail some degree of informal statistical reasoning and decision-making strategies. The game is not playing basketball per se, but taking on the role of a team owner or coach who needs to decide how best to compose a team given necessarily limited resources. The research team will provide a method for framing and researching statistical understanding and decision making of expert and novice players, then, based on the research, will develop scaffolded techniques for helping players become more reflective on and adept with the statistical knowledge and decision making strategies they use.

Proposal #: CNS 08-21527
PI(s): Raghavan, Padma
Chen, Long-Quing; Hudson, Peter J.; Kandemir, Mahmut T.; Smith, Brian K.
Institution: Pennsylvania State University
University Park, PA 16802-700
Title: MRI/Acq.: Acq.of A Scalable Instrument for Discovery through Computing
MRI Acquisition of a Scalable Instrument for Discovery through Computing

This award from the Major Research Instrumentation Program (MRI)
provides funds for the acquisition of a terascale advanced computing
instrument at the Pennsylvania State University. The instrument
will enable researchers from seven disciplines (biological, materials
and social sciences, computer and information science, engineering,
education, and geosciences), to perform virtual experiments toward
discovery and design through computing. Research projects concern:
predictive network modeling of infectious disease dynamics, designing
new piezoelectric materials, designing next-generation chip
multiprocessors, modeling human interactions to promote learning
in virtual communities, and the development of a critical zone
environmental observatory. Despite their diversity, these projects
share computational scalability challenges to be addressed for
enabling scientific advances that often depend on solving large
problems representing a sufficient level of detail and complexity.
The instrument will form the core of a multidisciplinary collaborative
environment to enable transformative approaches to address the
challenges of scaling at multiple levels. It will support a set of
integrated research, education, training, and outreach activities
to: (i) enable collaborative scaling across projects through the
transfer of scaling approaches from one domain into another, while
addressing algorithmic, system, or instrument scaling challenges
within individual projects, (ii) promote technology-transfer through
industrial partnerships, and (iii) grow and enhance the diversity
of the limited computational science talent pool.

Biostatistics is a vital component of all aspects of well designed cancer research. The Biostatistics Core provides HCCC investigators with a shared resource that assists with study design and statistical analysis of basic, clinical, and population-based studies. The core includes four experienced biostatisticians, and promotes and maintains an environment in which HCCC investigators feel free to involve the Biostatistics Core at all stages of research activity where statistical input might be beneficial. The Biostatistics core 1) Collaborates with HCCC investigators in the design of clinical, epidemiologic, basic science research and quality of life projects 2) Collaborates with HCCC investigators in the analysis of data from clinical, epidemiologic, and basic science projects 3) Conducts and participates in educational programs for investigators, faculty, fellows, students and staff of the HCCC 4) Supports the protocol review and study monitoring activities of the HCCC The Biostatistics Core also takes advantage of additional expertise found in the Department of Biostatistics at the University of Iowa College of Public Health, such as that needed in the analysis of microchip array data.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Prairie rattlesnakes, Crotalus viridis, are one of the most wide-ranging rattlesnakes in the world and are amongst the most wide-ranging of all venomous snakes. They are found from southern Alberta, Canada, throughout the western Great Plains and east slope of the Rocky Mountains southwards to northern Mexico. They are exposed to a wide variety of ecological situations and are likely to show high geographic variability in prey. We assume therefore that the composition of their venom should vary from site to site and that this variation could be elucidated by fractionating venom collected from snakes across their range. They also show high fidelity to densites and should therefore have relatively high amongst-population genetic variation. We initiated a pilot project in the summer of 2009, the purpose of which was to sequence DNA from a number of snakes and to discover whether we could successfully fractionate their venom. We collected blood and venom from snakes from some localities to investigate genetic variation amongst localities and variation in snake venom proteins amongst these localities. We were successful in sequencing DNA and in fractionating venom components but were hampered in our collection efforts by the cold summer experienced in much of the Great Plains in 2009. We did not sample enough populations, in our opinion, to draw robust conclusions but we are confident that our laboratory techniques work. This is of note because we are not familiar with any other labs that are studying variation in snake venom components.

DESCRIPTION (provided by applicant): Dysregulation of nitric oxide (NO) signaling is linked to various diseases including neurodegeneration, hypertension and stroke, heart disease, erectile dysfunction, gastrointestinal distress, and many forms of cancer. NO signaling begins in vivo with its synthesis by nitric oxide synthases (NOS). However, much is unknown regarding the catalytic and regulatory mechanisms of NOS enzymes. NOS enzymes catalyze the oxidation of arginine to NO and citrulline using oxygen and NADPH as cosubstrates in a two-step reaction with NG-hydroxyarginine, NHA, as an intermediate. Both steps occur in the heme-containing oxidase domain of NOS enzymes, which is fed electrons from a flavin-containing reductase domain. However, rate limiting electron transfer masks observation of the activated oxygen intermediates responsible for arginine and NHA oxidation. Knowledge of these intermediates is crucial to understand the catalytic mechanism of NOS enzymes. In Aims 1 and 2, these intermediates will be directly observed using novel spectroscopic techniques. NOS activity is regulated by variety of post-translational modifications (PTMs). Elucidation of the interplay between NOS modifications to control NO synthesis is a fertile area for research. In addition, targeting of PTMs instead of enzyme active sites is an orthogonal mechanism to treat diseases associated with dysregulation of NOS activity. Of the known modifications, inhibition of endothelial NOS (eNOS) by acetylation is the least characterized. Aim 3 will elucidate how acetylation works in concert with other PTMs to control eNOS activity. Specific aims: 1) Directly observe oxygen intermediates responsible for substrate oxidation. Photochemical inducible NOS (iNOS) enzymes will be designed wherein metallolabels deliver electrons rapidly to the heme upon excitation with light. These photochemical iNOS enzymes will then be utilized in 'flow-flash'spectroscopic investigations, wherein oxygen is bound to a ferrous heme, activated by photoinduced electron transfer, and probed with a variety of spectroscopic techniques. 2) Use non-natural substrate and heme analogs to probe oxygen activation. Non-natural substrate and heme analogs will be used to probe the structure-function and thermodynamic-kinetic relationships of oxygen activation in NOS enzymes using the techniques developed in Aim 1 and standard NOS assays. 3) Determine the mechanism of eNOS inhibition by acetylation in the context of other post-translational modifications. The precise sites of eNOS acetylation will be determined by mass spectrometry and then the mechanism of eNOS inhibition by acetylation will be determined. The effect of acetylation on other PTMs within eNOS will also be examined. PUBLIC HEALTH RELEVANCE: Nitric oxide is a gas similar in size to oxygen, a potent toxin, and a pollutant produced by automobile engines and cigarette smoke. In light of this, humans surprisingly produce nitric oxide to communicate between neurons, to open blood vessels, and as part of our immune response. In this proposal, I seek to understand how nitric oxide is produced by nitric oxide synthases, how nitric oxide production is controlled in humans, and how disruption of these processes can lead to diseases such as cancer, hypertension and stroke, gastrointestinal distress, heart disease, erectile dysfunction, and neurodegeneration.

"Bridging STEM to STE(A)M: Developing New Frameworks for ART/SCIENCE Pedagogy", hosted by the Rhode Island School of Design (RISD) will be a two-day workshop aimed to develop an innovative educational agenda that forges relationships between art and design disciplines and science, technology, engineering, and mathematics (STEM). The workshop will bring together leading scientists, IT experts and creative technologists, artists, designers, and education researchers to initiate discussions about how to bridge STEM education practices and creative problem-solving. As this innovative educational approach holds the potential to open new areas of exploration, and provide a platform and network for the further development of STEM to STE(A)M pedagogy. The long-term goals of this initiative are to: (1) Develop strategies for enhancing STEM education through the integration of art and design thinking (STEM + ART = STE(A)M); (2) Invent and share techniques that take advantage of simple, freely available IT systems and applications to support enhanced observation, analysis and understanding of pictorial and numerical data; (3) Build new connections between art and design disciplines and scientific fields to advance understanding of complex systems, e.g., through improved strategies and techniques for the shared perception and visualization of scientific data.

Methods and practices that promote shared ideas, insight, and language have the potential to alter STEM education and research practices in formal and informal settings. The diverse mix of disciplines and approaches represented at the workshop will give participants access to shared processes of inquiry into art/science pedagogy with the goal of achieving a high level of comprehensibility and knowledge sharing, broadening the accessibility and appeal of science, and transforming the discourse on STEM discovery and learning. As art thinking influences scientific thinking and vice versa, there is great potential for increased public understanding of science and scientific challenges. Workshop discussions will inform the creation of educational materials that exemplify interdisciplinary couplings between the arts and sciences. To begin to explore this potential, the Rhode Island School of Design (RISD) will develop prototype STE(A)M classes for high school students through a Pre-College summer program offered through RISD's Continuing Education division. In addition, in connection with the workshop, a new graduate-level course will be developed at RISD to prepare future artists and arts educators to lead successful arts/design/science collaborations. The broader intention of these prototype courses is to provide tangible examples that can prompt parallel developments at other institutions.

The Biostatistics and Bioinformatics Core (Biostats Core) provides collaborative statistical and informatics support to the UI/MC SPORE projects, developmental projects, and other cores. The comprehensive nature ofthe Core, which will have activities at both lowa and Maye, assures each SPORE investigator access to expertise that includes development of study designs and analysis plans, state of the art data analysis and interpretation, data management resources, and abstract and manuscript preparation. The Core builds upon the innovative and time-tested procedures and systems developed by Mayo Clinic, one ofthe largest statistical groups in the country whose members have collaborated on more than 8,000 clinical and basic science research studies since 1966, as well as the University of lowa Holden Comprehensive Cancer Center, Biostatistics Department, and Coordinated Laboratory fer Computational Genomics. Design and analysis support will be provided across a range of fields, including epidemiological studies, basic sciences including translational and immunologic correlative studies, gene microarray, gene and mutation discovery, expression analysis and genomics, and computational biology. The Core developed the statistical plans for past studies initiated in the SPORE, and has been actively involved in the preparation of statistical plans for the four projects in this application. Support is also provided for the management and integration ef existing and newly collected data through consistent and compatible data handling. Areas of support include database development, data form development and processing, data collection and entry, data archiving, quality control, and management of information relating to gene mutation identification and genotyping data for disease linkage experiments. In the past funding periods, the Cere established the infrastructure te link lymphoma clinical and research databases between Ul and MC. This system is fully functional and allows web-based clinical registration and data entry from both sites into a common database. Furthermore, the Core has and will continue to provide data management for all studies, to monitor adverse events In conjunction with the Clinical Research Core, and to prepare data summaries for manuscript preparation. In summary, strengths of the Biostatistics and Bioinformatics Core are our collaboration with each of the projects and cores, the ability to utilize the established centralized research database as well as the operational and statistical infrastructure already in place in the SPORE, and the breadth of expertise provided by Biostatistics and Bioinformatics personnel.

The PIs and Co-PIs of grants supported through the NSF-NIH-ANR-BMBF-BSF Collaborative Research in Computational Neuroscience (CRCNS) program meet annually. This tenth meeting of CRCNS investigators brings together a broad spectrum of computational neuroscience researchers supported by the program, and includes poster presentations, talks, plenary lectures, and workshops. The meeting is scheduled for October 16-18, 2014 and is hosted by Arizona State University.

Bronchopulmonary dysplasia (BPD) is defined by the NIH as mild, moderate, or severe based on the required respiratory support at 36 weeks adjusted age. 1 An NIH workshop proposed a severity-based definition that classifies BPD into mild, moderate or severe based on either postnatal age or PMA (Table 2-1). Mild BPD was defined as a need for supplemental oxygen {02) for~ 28 days but not at 36 weeks PMA or discharge, moderate BPD as 0 2 for~ 28 days plus treatment with <30% 0 2 at 36 weeks PMA, and severe BPD as 0 2 for~ 28 days plus~ 30% 0 2 and/or positive pressure at 36 weeks PMA. Ehrenkranz et af validated the NICHD severity-based definition ofBPD by comparing it to the more traditional definitions ofBPD such as supplemental oxygen at 28 days and at 36 weeks PMA. The NICHD consensus severity based scale better identified infants who are at most risk for poor pulmonary outcomes as well as neurodevelopment impairment than the traditional definitions

This project was developed during a NSF Ideas Lab on "Cracking the Olfactory Code" and is jointly funded by the Chemistry of Life Processes program in the Chemistry Division, the Mathematical Biology program in the Division of Mathematical Sciences, the Physics of Living Systems program in the Physics Division, the Neural Systems Cluster in the Division of Integrative Organismal Systems, the Division of Biological Infrastructure, and the Division of Emerging Frontiers. The sense of smell is essential for maintaining quality of life in humans, and its decline can be an important harbinger of neurodegenerative disease. Moreover, since nearly all animals aside from primates rely on olfaction for most survival functions, understanding chemical sensing has immense practical value, for example, in the control of agricultural pests or in training animals to detect odors relevant for bomb, drug and cancer detection. In spite of its importance, the understanding of olfaction lags far behind the other senses, which is in part due to the lack of understanding of the physical space of odors. The understanding of the neural bases of vision and audition were greatly advanced by investigations of the physical dimensions of visual and auditory stimuli. It is therefore likely that a similar in-depth investigation of odor space - how natural odors occur and the backgrounds against which they must be detected - will reveal a new depth of richness of neural representations of odors in the brain. Insects such as the fruit fly and honey bee are excellent models for this research because of the accessibility of their central nervous systems, because of their ease of use under controlled laboratory conditions, and because of the functional similarity of how odors are processed in insect and mammalian brains. This research will characterize how odor flowers and fruits with respect to behavioral value for honey bees (food) and fruit flies (food and egg laying sites). Further monitoring of neural activity in early and later stage processing in the brain, when combined with computational modeling, will reveal significantly richer neural representations than have heretofore been described. This new understanding stands to have an impact on understanding how healthy brains encode sensations and memories of odors and how brains fail under disease conditions. It will also have an impact on understanding how the sense of smell may be built into engineered devices. Finally, both insects are also of economic importance to agriculture for crop pollination (honey bees) and damage to fruit (fruit flies). The PIs will teach and work with undergraduate, graduate and postdoctoral students and especially recruit students from underrepresented groups in science.

This research will quantitatively characterize the real-world statistics of multi-component natural odor scenes and investigate how they drive behavior and processing in several brain regions. The focus will be on honey bee as well as fruit fly adults and larva as models, where it will be possible to characterize a library of ethologically relevant natural odors associated with a diversity of behavioral outputs. The work will begin by quantitatively characterizing the detailed statistical properties of natural odor scenes in defined ethological contexts. This will build on the rich literature on identified natural odors in insects and mammals. Naturally occurring plant and fruit odor samples from the natural environments of each insect will be collected and chemically analyzed. Nonlinear dimensionality reduction techniques and approaches based on sparse coding will determine the dimensions of odor space that are most salient for behavioral decisions. Such a quantitative deconstruction of the sensory input would be unprecedented in olfactory neuroscience, and should allow the PIs to effectively and comprehensively drive olfactory circuits for the first time. The hypothesis is that the stimulus dimensions that are most behaviorally relevant to the animal will be most efficiently extracted by the olfactory system. Synthetic odor blends will be specially constructed to vary along relevant sensory dimensions, to probe neural codes and adaptive behaviors in the olfactory system. As in research on the visual system, analysis of such evoked neural responses using statistical methods that take into account natural odor statistics will reveal novel olfactory computations and behaviors that have been previously inaccessible. The project will generate datasets of immediate use and importance to scientists in theoretical biology and mathematics, engineering and biology.

The Cyberlearning and Future Learning Technologies Program funds efforts that will help envision the next generation of learning technologies and advance what we know about how people learn in technology-rich environments. Cyberlearning Exploration (EXP) Projects explore the viability of new kinds of learning technologies by designing and building new kinds of learning technologies and studying their possibilities for fostering learning and challenges to using them effectively. This particular project will develop educational games that adapt to the skill level of the user and will conduct research on using them to teach concepts from computer programming.

Modern computing is increasingly handled in a parallel fashion and despite the growing body of work on how to teach parallel programming, little is understood about the learning of this subject. This project will shed light on the challenge of learning parallel programming and gather initial data on ways to scaffold it in college-level courses. We propose to develop a genre of adaptive learning games in which we will gather data on how experts and novices address parallel programming problems and study ways to scaffold learning. Our research will advance understandings of how people learn concepts associated with parallel programming, as well as investigating which activities enhance the learning process in this domain. We will generate content tailored to specific students through a method entitled procedural content generation. This work will transform the transition from sequential programming to parallel programming in undergraduate computer science curricula and advance personalized learning. We will disseminate our prototype and results via the CSinParallel network, an NSF-funded national organization that works to introduce concurrent, parallel, and distributed computing concepts into a greater percentage of computer science curricula. The research will further our understanding of how students learn parallel programming concepts and contribute to training a competitive workforce that is better prepared for today's parallel computing world.

? DESCRIPTION (provided by applicant): The ribosome is a complex ribonucleoprotein (RNP) responsible for the essential process of protein synthesis in all living organisms. Assembly of ribosomes involves the transcription and processing of ribosomal RNAs (rRNAs), association of ribosomal proteins, and the activities of many assembly factors. Defects in the ribosome assembly process are associated with changes in virulence and drug resistance in various human pathogens. Alterations in rRNA maturation and thus with associated nucleases, which are involved in this process, have been implicated as being very important for pathogenicity. A clear understanding of this biogenesis cascade will be needed for the development of novel antimicrobial drugs. However, many questions remain regarding the mechanism of rRNA maturation and exactly how this process fits into the ribosome biogenesis cascade. To address these questions the Culver laboratory has developed a novel affinity purification technique to isolate pre-SSU assembly intermediates from E. coli. Purified pre-SSUs from wild-type E. coli contain an precursor 17S rRNA that upon incubation with cell extracts or purified rRNA processing enzymes is processed into mature 16S rRNA. Thus these data suggest that purified RNPs are on- pathway assembly intermediates that can undergo maturation in vitro. Therefore, this proposal seeks to determine how rRNA processing is integrated into small ribosomal subunit (SSU) biogenesis and to decipher the complete mechanism of SSU 16S rRNA maturation in E. coli using this affinity purification method. Aim1 of this proposal is to isolate nd characterize pre-SSU intermediates from mutant E. coli strains perturbed for SSU biogenesis in which distinct rRNA processing intermediates accumulate. Further characterization of these intermediates will divulge the composition of in vivo formed RNPs that are the substrates for rRNA processing and reveal critical assembly events that occur downstream of rRNA cleavage. Secondly, using these purified pre-SSUs as substrates, Aim 2 of this proposal will focus on using cell extracts and purified rRNA processing enzymes to kinetically characterize the molecular mechanism of 16S rRNA maturation in vitro. These data will serve as a foundation for understanding the flux of rRNA processing pathways under various conditions and allow the individual roles of rRNA maturation enzymes to be dissected. Taken together these aims seek to provide an unprecedented glimpse into the mechanism of 16S rRNA maturation and SSU biogenesis in E. coli.

Visible light is one of the primary ways we get information about the world and the universe, for example using microscopes and telescopes. Light pulses are also used to convey information across the globe at unprecedented rates using the world-wide fiber-optical network that supports the Internet, e-commerce, and even the international financial markets. Furthermore, light can be used to control material systems with applications ranging from laser eye surgery to optical "tweezers" that can trap and manipulate individual molecules. Many of these developments have been enabled by new methods to generate, manipulate and detect light. Today, researchers are developing means to generate, control, and measure the fundamental constituents of light, single photons (individual light "particles"), which obey the laws of quantum physics. This project will explore methods to produce, manipulate and measure individual photons with well-defined pulse characteristics (color and temporal pulse shape) and examine the potential of such single-photon pulses for applications such as secure communications, enhanced precision measurements, and high-capacity computation. The project supports education through training of a diverse group of undergraduate, graduate, and post-doctoral researchers in the field of quantum information science, and provides outreach to local high schools and colleges.

This project aims to harness the potential advances in quantum technologies offered by encoding information in the wavelength and temporal shape of individual photons. By exploring methods to produce, manipulate and measure single photons with well-defined pulse characteristics (wavelength and temporal shape), this research program will examine the impact of spectral-temporal single-photon encoding for improved performance in applications such as sensing and quantum communication. To address these goals, the project explores wave-guided optical sources of controllable spectral-temporal entangled photon pairs based upon spontaneous nonlinear optical processes. It examines methods for manipulating single-photon pulses by application of well-defined temporal and spectral phase implemented using electro-optic phase modulators and engineered spectral dispersion in optical fibers. It also investigates methods to characterize the pulse-mode structure of one and two photons by temporal- and spectral-shearing interferometry. This platform for information encoding in the single-photon spectral-temporal shape offers increased information capacity for single photons in integrated-optical systems.

The Biostatistics Core (Biostats) is a centralized and dedicated resource structured to meet biostatistical needs of the Holden Comprehensive Cancer Center (HCCC). Quality biostatistical support promotes good study design, efficient use of resources, and effective analysis of data. Biostats provides such support in close collaborations with HCCC members, other shared research resources, and administration to advance the research and education missions of the HCCC. The comprehensive nature of Biostats assures cost-effective access to biostatistical support that includes study design and development; protocol review and study monitoring; research data management; statistical analysis and programming; analysis reporting and publication; methodological development; and education, training, and professional development. The primary resources of Biostats are the expertise and time of its biostatistician personnel. In order to meet HCCC biostatistical needs, Biostats includes personnel who have a wide range of expertise, including experimental design, clinical trials, statistical computing, spatially and temporally correlated data analysis, genetic and genomic data analysis, and Bayesian statistics. Personnel are active participants in multiple aspects of the HCCC. They serve on the HCCC Protocol Review and Monitoring Committee and the Data Safety and Monitoring Committee. In the current grant period, they collaborated with 73 HCCC investigators on 269 research projects, including 37 investigator-initiated clinical trials. Collaborations involved all research programs and close interactions with the Bioinformatics Shared Resource, Population Research Core, and Molecular Epidemiologic Resource, as well as the Clinical Research Support Office. Additionally, Biostats provided educational training and professional development. It advised 31 trainees on biostatistical methods and results related to supported projects, gave seminars, and conducted a biostatistics course for trainees. In summary, Biostats is a highly collaborative, productive, and integrated resource that is vital for the HCCC.

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Carey Johnson from the University of Kansas, Dr. Brian Smith from Medical College of Wisconsin, and Dr. David Arnett from Northwestern College. The project investigates shapes (conformations) and shape changes of the enzyme nitric oxide synthase (NOS). The importance of conformational changes in the function of complex enzymes like NOS has become increasingly recognized. NOS activity requires a sequence of electron transfers between different domains of the enzyme. The hypothesis is that these events are controlled by conformational dynamics. In this project, the conformations and conformational changes of NOS are tracked by time-resolved and single-molecule fluorescence techniques. Mass spectrometry shows how domain interactions are regulated by binding to NOS of a calcium signaling protein, calmodulin. The results may show how multi-domain enzymes function through conformational changes. The project provides training in advanced fluorescence and mass spectrometric techniques for graduate students at Kansas University and the Medical College of Wisconsin. Undergraduate students from all participating institutions are trained in interdisciplinary science research. The project also offers training for members of the UKanTeach program which trains science majors as high school science teachers.

This project exploits the spatial and temporal resolution inherent in time-resolved and single-molecule fluorescence to identify and track the conformational states of nitric oxide synthase (NOS). NOS is a homodimeric enzyme that catalyzes formation of nitric oxide by shuttling electrons from modules in one monomer to the heme in the oxygenase domain of the other. Electron transfer in both domains depends on calmodulin binding. Because electron transfer only occurs when the electron donor and electron acceptor are in close proximity, conformational changes must occur to bring different donor and acceptor couples together sequentially. The time scales of interchange among conformational states are not known, nor is it clear how the observed conformational changes correlate with the catalytic cycle of the enzyme. The methods of the project correlate conformations and dynamics detected by fluorescence with knowledge of inter-domain interactions at the peptide level. These inter-domain interactions are observed from hydrogen-deuterium exchange (HDX) mass spectrometry. To identify and assign conformational states observed, selected site-directed mutants that disrupt specific subdomain interactions are probed by both fluorescence and mass spectrometry. The project may lead to a detailed model of NOS function that describes the conformational sequences and rates of conformational changes. The project may also demonstrate how the conformational sequences are related to enzyme regulation. The project provides training in advanced fluorescence and mass spectrometric techniques for graduate students at Kansas University and the Medical College of Wisconsin. Undergraduate students from all participating institutions are trained in interdisciplinary science research. The project also offers training for members of the UKanTeach program which trains science majors as high school science teachers.

There are over 10,000 species of birds and they are found in nearly every terrestrial environment. This remarkable diversity has served as a critical component of enhancing public engagement with science and nature, as evidenced by the multi-billion dollar output generated by bird-watching activities in the US economy. Birds exhibit complex behaviors, elaborate physical characteristics, and impressive adaptations, which has made them a major focus of modern scientific research. In current research, birds are a model system for comparative studies on a range of fundamental topics in biology. However, the missing piece of this otherwise powerful comparative biology toolkit is an accurate and complete description of the evolutionary relationships (phylogeny) among all bird species, i.e., an avian tree of life. This project will collect DNA data to fill this gap by producing a complete tree of life for all bird species in order to test hypotheses regarding the origins, diversification, and dispersal of birds around the planet. A complete tree will be transformative to fields like ornithology and evolutionary biology. This project will help prepare the next-generation of biodiversity scientists by training undergraduate, graduate, and post-doctoral scientists, and also will include numerous public outreach components including exhibits and videos. Developing learning modules and working with teachers will help bring the research into the classroom, reaching a diversity of students in several states. Finally, the researchers will make all data collected from each bird immediately available to the scientific community and the public to enable broad-scale comparative analyses and integration with other avian data sets.

"Big trees" - comprehensive species-level phylogenies - are revolutionizing the field of evolutionary biology. This project will generate genome-wide markers for 8,000 species of birds and leverage data products from other NSF-supported studies to produce a phylogenetic hypothesis for all 10,560 bird species. A well-resolved, complete, time-calibrated, species-level phylogeny of birds will allow numerous challenging hypotheses to be tested, provide the conceptual foundation for a phylogenetic revision of bird taxonomy, and permit transformative analyses aimed at elucidating the processes that generate biological diversity. Specific hypotheses to be tested using phylogenies generated by this project include 1) Neoaves underwent a rapid radiation after the K-Pg mass extinction, 2) avian diversification has been shaped by the history of intercontinental dispersal, and 3) species tree methods outperform concatenation in phylogenetic analyses of genome-scale data.

ABSTRACT: Core C: Biostatistics and Bioinformatics. The Biostatistics and Bioinformatics Core (Core) provides collaborative statistical and informatics support to SPORE projects, developmental projects, and other cores. The comprehensive nature of the Core, which will have activities at both Iowa and Mayo, assures each SPORE investigator access to expertise that includes development of study designs and analysis plans, state of the art data analysis and interpretation, data management resources, and abstract and manuscript preparation. The Core builds upon the innovative and time-tested procedures and systems developed by the Division of Biomedical Statistics and Informatics at Mayo Clinic, one of the largest analytical groups in the country whose members have collaborated on more than 8,000 clinical and basic science research studies since 1966, as well as the Holden Comprehensive Cancer Center and the Biostatistics Department at the University of Iowa. For this funding cycle, we added a senior Bioinformaticist staff as a Core member for the proposed sequencing methods in the projects. The Core members will provide design and analysis support across a range of fields, including epidemiological studies, basic sciences including translational and immunologic correlative studies, gene microarray, gene and mutation discovery, expression analysis and genomics, and computational biology. The Core developed the statistical plans for past studies initiated in the SPORE, and has been actively involved in the preparation of statistical plans for the four projects in this application. Support is also provided for the management and integration of existing and newly collected data through consistent and compatible data handling. Areas of support include database development, data form development and processing, data collection and entry, data archiving, quality control, and management of information relating to gene mutation identification and genotyping data for disease linkage experiments. In the past funding periods, the Core developed and maintained the infrastructure to link lymphoma clinical and research databases between University of Iowa and Mayo Clinic. This system is fully functional and allows web-based clinical registration and data entry from both sites into a common database. Furthermore, the Core has and will continue to provide data management for all studies, to monitor adverse events in conjunction with the Clinical Research Core, and to prepare data summaries for manuscript preparation. In summary, strengths of the Biostatistics and Bioinformatics Core are our collaboration with each of the projects and cores, the ability to utilize the established centralized research database as well as the operational and statistical infrastructure already in place in the SPORE, and the breadth of expertise provided by Biostatistics and Bioinformatics personnel. 

This award in the Research Advanced by Interdisciplinary Science and Engineering (RAISE) on Transformational Advances in Quantum Systems (TAQS) program supports collaborative work by Professors Michael Raymer, Andrew Marcus and Brian Smith at the University of Oregon to demonstrate experimentally improved performance in the sensing of remote objects and the spectroscopy of electronically coupled molecules using quantum mechanical states of light. Advancements in nonlinear optical spectroscopy and metrology that rely on intrinsically quantum mechanical effects are of broad scientific interest to the chemistry, physics and engineering communities. The methods and research so developed will create new opportunities that may be utilized in the expanding interdisciplinary field of quantum information science. The supported research will facilitate the dissemination of results at international meetings and workshops, and the tools developed will be made readily available to the scientific community. The three PIs will collaborate on all aspects of the proposed work, and will co-advise the PhD students working on the projects. The students involved will thus enjoy a unique and broad exposure to research training that spans quantum optics, ultrafast molecular spectroscopy, and biophysics.

An interdisciplinary team spanning chemistry, physics, and engineering in the Oregon Center for Optical, Molecular, and Quantum Science, will carry out experiments to demonstrate that Einstein-Podolsky-Rosen (EPR)-like entanglement of photons in the time-frequency domain can provide a significant quantum advantage in spectroscopy and metrology. Time-frequency entangled photon pairs (EPP) are tightly correlated in time while being anti-correlated in frequency, such that the sum of the energies of the photon pair is sharply defined. Such quantum states of light offer the ability to circumvent classical Fourier time-bandwidth limits when employing photon coincidence events, either in detection, as in standard quantum optics, or in two-photon excitation of molecular complexes, as in nonlinear spectroscopy. The research will investigate potential quantum advantages in the context of four related optical schemes in metrology and nonlinear spectroscopy: 1) Quantum illumination (sensing of an object's presence or absence); 2) Multi-parameter estimation of complementary parameters (e.g., estimating the distance and velocity of a reflecting object); 3) Two-photon interferometric nonlinear spectroscopy; and 4) Entangled photon-pair 2D fluorescence spectroscopy. The commonality that unifies the four schemes is the use of broad-band (multi-spectral-mode), time-frequency EPP produced by spontaneous parametric down-conversion (SPDC), coupled with interferometer configurations that exploit quantum interference.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Contact PD/PI: Sherwin, Robert S. 1. Overall Project Summary- The Yale Center for Clinical Investigation (YCCI) was created in 2005 to strengthen Yale's infrastructure for clinical and translational research, based on the recommendation of a Medical School strategic planning committee. Soon afterwards, when NIH launched its new program of Clinical & Translational Science Awards, YCCI applied and became the home of the Yale CTSA. Since then, one of its major priorities has been to support the education and career development of the next generation of clinical and translational investigators. As described in the present application, this initiative has met with great success, underscored by the fact that graduates of YCCI's K-Scholar program have received 47 individual NIH K Awards, 43 NIH RO1 awards, and 65 Foundation grants, published >1,800 papers, and obtained >$240 million in independent research funding. Remarkably, 98% of the program's graduates have stayed in academic medicine or pursued research careers in the biotech or pharmaceutical industries. YCCI has also made substantial progress in its push to accelerate the translation of disease-related discoveries into the clinic. As will be described, it provides Yale investigators with key assistance in areas including biostatistics and bioinformatics, study design, protocol development, regulatory approval, patient recruitment, access to inpatient and outpatient research facilities, and budgeting support, and gives them ready access to pilot grants and state-of-the-art research cores. The result has been a significant upsurge in the number and scope of clinical research projects throughout the Medical Center. In the next grant cycle, YCCI will build upon these achievements with an emphasis on team-based T1 to T4 research, including studies across the lifespan. YCCI will also pursue new partnerships with the Yale School of Engineering & Applied Science to develop an innovative technology transfer program called the Center for Biological and Innovative Technology (CBIT) and with the School of Organization & Management to offer a novel program of leadership training for clinicians and physician-scientists. In addition, YCCI will take active advantage of the recent expansion of clinical services by Yale-New Haven Hospital (YNHH), which now has 1,540 beds and more than 1 million outpatients visits per year, and the growth of the Yale Medical Group (YMG), which has a network of >1,200 practicing physicians in >100 clinical specialties. The resulting clinical volume (~4 million patient records) gives Yale researchers access to a large, diverse patient base for outcomes studies and clinical trials. Overall, YCCI will leverage Yale's outstanding scientific and clinical environment and work with other CTSA hubs to foster the growth of multidisciplinary team science, to develop innovative strategies for disease prevention, diagnostics, and therapeutics, and to implement results for the benefit of the health care system and the population as a whole. Project Summary/Abstract Page 220 Contact PD/PI: Sherwin, Robert S. Program Narrative Yale Center for Clinical Investigation (YCCI) is a leader in team-based T1 to T4 research, including studies across the lifespan. YCCI will leverage Yale University's outstanding scientific and clinical environment and work with other CTSA hubs to foster the growth of multidisciplinary team science, to develop innovative strategies for disease prevention, diagnostics, and therapeutics, and to implement results for the benefit of the health care system and the population as a whole.

The exploitation of the inherent quantum nature of systems holds great promise in enabling quantum technologies that far surpass our current systems. There remain significant barriers to reaching this goal. In the area of quantum simulation and modeling, there is a need for new quantum platforms that go beyond our current few-qubit systems as well as the development of algorithms to efficiently use those platforms. Development in sensing that shows quantum advantage is just now becoming possible, opening up the possibility of quantum sensors that can be deployed outside of the laboratory. Systems using quantum entanglement have demonstrated quantum communication, but much work is needed on quantum repeaters and the range of wavelengths to make such systems commercially viable. This research in quantum information science forms the Quantum Leap NSF Big Idea.

Understanding and controlling quantum systems is critical to achieving the next generation in quantum computing, sensing and communication. The National Quantum Initiative Act tasked the NSF to carry out a basic research and education effort in the area of quantum information science. As part of that effort, NSF has made a number of awards in quantum information science, including the funding of three Quantum Leap Challenge Institutes. In order to introduce these new institutes, highlight NSF efforts in this area and facilitate communication between researchers, NSF will hold a virtual grantees workshop in Fall of 2020. This award will enable that effort. The meeting will be held over two days, September 29-30, 2020. It is anticipated that there will be over 100 participants. There will be plenary talks introducing the Quantum Leap Challenge Institutes and parallel sessions by grantees in the area of quantum information science. These talks will range from quantum communication, sensing, computation, simulations as well as the development of new quantum platforms.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

The Odor2Action network consists of 16 investigators from 16 research institutions in the United States, the United Kingdom, and Canada. The composition and scientific goals of the effort are designed to leverage prior investments in neurotechnologies funded by the BRAIN Initiative, other domestic agencies and international partners. Specifically, Odor2Action will address a central question of neuroscience: How do animals use information from odor stimuli in their environment to guide natural behaviors? To synergistically study this problem, the network is subdivided into three interdisciplinary research groups (IRGs); each IRG contains experts in a wide range of experimental and theoretical approaches, and investigates how similar problems are solved by nervous systems in phylogenetically diverse species. IRG1 will test a novel framework for organizing olfactory stimulus space and olfactory codes around the statistical relationships among natural odors. IRG2 will work to understand how neural circuits translate odor signals into dynamic and adaptive behaviors, a critical component of our overall network goal of understanding how natural odors trigger natural behaviors. IRG3 will investigate the physical structure of odor environments and how animal motion and sensory capabilities interact with those environments to detect, discriminate and localize odor objects. Collectively, the network will determine how neural representations of odor are generated, how they are progressively reformatted across successive circuit layers, and how they support useful behaviors. While focusing on olfaction, this project will provide broad and fundamental insights into brain function. This compact circuit architecture associated with olfaction offers unique opportunities to achieve an end-to-end understanding of the core computational logic by which various brains organize and read out such high-dimensional, discrete variables to generate adaptive behaviors. This coordinated project on the neuroscience of olfaction across species will have important societal impacts in science, technology, health, and policy. Given the complexity and high dimensionality of chemical space and its primacy in driving behavior among most species, studying how odor leads to action promises to provide insight into optimal biological solutions for encoding complex information about the external world. Elucidating biological solutions to olfaction can inform the development of algorithms and engineered devices for detection and identification of chemicals in applications that span the range from homeland security to food safety.

The Odor2Action network will address a central question of neuroscience: How do animals use information from odor stimuli in their environment to guide natural behaviors? The network will approach this problem in the context of olfactory-guided behavior as an instance of a much more general problem of many complex brain systems - how are high-dimensional, discrete, and combinatorial variables that are not simply ordered along easily discernible axes represented in brain circuits and mapped to actions? The compact olfactory circuit architecture offers unique opportunities to achieve an end-to-end understanding of the core computational logic by which brains organize and read out such high-dimensional, discrete variables to generate adaptive behaviors. This network will study olfactory systems of mammals and insects, which have independently evolved common structural elements at successive levels of olfactory processing in their central nervous systems. These common elements possibly reflect convergent evolution towards a set of similar solutions to shared olfactory problems. The network comprises three interdisciplinary research groups (IRGs) that are designed around specific elements of an end-to-end investigation of olfaction. IRG1 aims to understand the first stages of how neural representations of odor are generated, and how they are progressively reformatted across successive circuit layers to support meaningful behaviors. IRG2 aims to understand how neural circuits translate odor signals into dynamic and adaptive behaviors, a critical component of our overall network goal of understanding how natural odors trigger natural behaviors. IRG3 will investigate the physical structure of odor environments and how animal motion and sensory capabilities interact with those environments to detect, discriminate and localize odor objects. Each IRG integrates theory and experimental approaches in two or more species in ways that produce complementary, synergistic interactions across levels of biological analysis.

This Neuronex award is co-funded by the Division of Emerging Frontiers and the Behavioral Systems Cluster within the Directorate for Biological Sciences, the Office of Advanced Cyberinfrastructure within the Directorate for Computer and Information Sciences, the Mathematical Biology Program and the Physics of Living Systems Program within the Directorate for Mathematical and Physical Sciences, as part of the BRAIN Initiative and NSF's Understanding the Brain activities.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Traditional museum specimens (e.g., skins, skeletons, dry- and fluid-preserved specimens), once considered poor sources of DNA, are now becoming recognized as a potential vast biological resource for historical DNA (hDNA), that provide an unparalleled record of biodiversity spanning the last 200 years. In particular, the advent of high-throughput sequencing platforms (using short DNA fragments) now provides a more efficient means of sampling the hDNA genome. However, hDNA?s potential has hardly yet been explored, with current procedures for DNA extraction often relying on approaches tested on few individuals and optimized for specific projects. Consequently, outcomes of most extraction efforts still often lead to unusable sequence data, or otherwise, high sequencing errors, missing data, and/or contamination. This project will develop efficient and open-source protocols for yielding usable genome-scale molecular data from typical traditional museum specimens, based on rigorous comparative experiments of existing and novel DNA extraction methods, using time-series collections at the American Museum of Natural History (AMNH). Broader societal impacts include conservation (using museum specimens to document historical trends in populations and emerging diseases), forensics (providing improved methods for accurate species identification of biological material), and genomics (documenting genetic change over the past 200 years).

Project outcomes will determine optimal tissue sources and extraction methods for hDNA, develop improved methods for reverse crosslinking of formalin-fixed DNA, and provide a deeper understanding of how DNA degrades due to exposure to formalin, alcohol, tissue buffers, and archival storage time. This project will also develop new approaches for bioinformatic processing of hDNA, to better detect contamination, evaluate the effects of hDNA on phylogenetic inference, and improve the utility of hDNA in all aspects of comparative biology. The application of reliable bioinformatic processing pipelines produced from this study will scale-up the availability of genetic research resources by at least 100-fold (e.g., at AMNH, 120,000 current DNA tissue samples compared to >20 million biological museum vouchers). The availability of DNA from historical museum specimens will also allow the genetics and epigenetics of extinct species and populations to be studied and provide exciting new opportunities to determine how genetic diversity has changed during the Anthropocene. Results of the project will be provided at https://www.amnh.org/research.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Quantum information science and technology (QIST) holds promise to transform radically our technological landscape by developing new computational, communications and sensing modalities as identified in the National Quantum Initiative. The potential long-term impacts on national needs of QIST are diverse and include enhancing scientific progress as well as economic and national security. Quantum Interconnects (QuICs), which enable transferring quantum information between different physical systems, are an essential class of components needed for the realization of QIST. The team will develop and demonstrate a novel interface between neutral atoms and photons, or light ‘particles’. Our approach is based on generating a correlated system of atoms and photons, known as a cluster state, that can be used for quantum computation, sensing and communications. By utilizing an integrated-optics (on-chip) platform to manipulate photons at telecommunications wavelengths, the PI and his collaborators aim to develop a system that can be readily deployed in quantum network applications. The impacts on basic science and engineering will be significant. For example, our work enables new ways to create and control large quantum systems, which could provide new approaches to simulate nature. This project contributes to a diverse quantum-ready workforce through training of graduate and undergraduate students and range of outreach activities.

To produce neutral-atom-photonic cluster states this project combines the deterministic generation of primitive photonic cluster states via light single-atom emission with an integrated-optics platform. All-optical operations will be implemented on-chip to combine (‘fuse’) the primitive cluster states into larger ones that can serve for quantum information processing and enable overcoming loss in a quantum network. Specifically,the primitive photonic cluster states are generated by photon emission from single neutral rubidium atoms that are laser-trapped and strongly coupled to separate optical cavities defined in a common nanophotonic-crystal waveguide fabricated in silicon nitride. Laser and microwave controls cause the atom(s) to emit deterministically a sequence of single-photon wave packets that propagate along the waveguide axis. The photons carry information about the atomic state in their emission time. Photons can occupy a superposition of these ‘time bins’, corresponding to a time-bin quantum bit (‘qubit’). The photons are coupled into an external integrated-optics chip containing fast switches for combining the photon packets with appropriate delays designed for photonic ‘fusion gate’ operations, which are implemented by detecting a subset of photon outputs from the chip.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Quantum information science and technology (QIST) is a rapidly evolving field of interdisciplinary research that aims to harness the behavior of quantum systems to enable new capabilities for a range of applications including computation, communications, and sensing. A variety of physical systems are being explored for their potential to encode and manipulate quantum bits (qubits), each of which presents different advantages and challenges. Within QIST, light plays an important role in the transport and extraction of quantum information. To date most approaches to encoding quantum information in light fields has focused on polarization and spatial profile of light beams, which are not compatible with optical fiber networks that will form the backbone of a future quantum Internet. In this project the group will develop an experimental platform to encode quantum information in temporal modes of quantum light, where the temporal shape and color of a photon, a light ‘particle,’ carries information. Quantum applications enabled by temporal mode encoding include linear optics quantum computing, quantum communications, sensing, and simulations. Beyond the scientific and technological impacts, this project will contribute to a quantum-ready workforce through training of graduate and undergraduate students.

This project will develop methods to control and measure pulses of light at the single-photon level and its application to perform targeted operations for quantum information applications. Common approaches to shape optical laser pulses, which employ filtering or amplification, are not compatible with quantum light. To address the temporal modes of light thus requires unitary (phase only) transformations that modify the spectral and temporal phase of the light pulses. For quantum applications most efforts have focused on nonlinear optical means for pulse control. Here the group will use linear-optical methods with electro-optic temporal phase modulation and dispersive spectral phase. The overarching research goal is the implementation of unitary transformations on temporal modes. The proposed approach is to realize such temporal mode transformations by the sequential application of temporal phase modulation and spectral dispersion using off-the-shelf components. To overcome challenges in timing instability that arise in the application of temporal phase using electro-optic modulators, the radio-frequency driving field will be directly generated from the optical pulses that generate the single photons to be manipulated. To verify that the targeted temporal mode transformations are experimentally implemented, an approach to characterize the transformations – a technique known as quantum process tomography – based upon spectral interferometry will be developed.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Animals develop an understanding of their environment through learning that specific cues in the environment are reliably paired with and consequently predict important outcomes, such as access to food or the presence of danger. The concept of outcome expectation based on these predictions has been influential in the development of studies of associative learning in mammals. These analyses have had a profound impact on understanding of outcome-related behavior in humans, including monetary rewards and the consequences of traumatic experiences, and for pathologies of the reward systems in the brain. The neural underpinnings of outcome expectation are particularly challenging to study in mammals because of the requirement for exquisite cellular, temporal, and genetic specificity of experimental manipulations. The fruit fly Drosophila melanogaster has been a valuable model for investigating the genetic and neural bases that underlie learning and memory, including learning of cue-outcome associations. The recent development of work with identified neurons and their detailed connections in the fly brain makes the larval and adult fruit fly brains ripe as models for advancing understanding of neural bases for outcome expectation learning in mammals. Using the powerful experimental approaches available in the fruit fly model system and resources guided by computational modeling, the team of researchers investigate complex memory representations in Drosophila. This project also provides interdisciplinary training for postdoctoral researchers, and graduate and undergraduate students, development of new K-12 biology classroom material, and collaboration with Arizona State University’s award-winning Ask-A-Biologist program.

Early and most current studies of learning and memory in the fruit fly (Drosophila melanogaster) use basic behavior conditioning protocols to study learning in controlled laboratory settings. The ability to transgenically manipulate many of the brain neurons in the fruit fly with exquisite specificity, and the recent knowledge of the synaptic ‘connectome’ of the fruit fly brain, makes these animals almost unique as a comprehensive model for studies of learning, memory and motivated behavior. Within this context, the investigators propose that studies of learning and memory will be greatly enhanced by using more sophisticated means for evaluating memory representations, and by combining those studies with information from the connectome guided by computational modelling. To that end, the investigators examine the function of reinforcement pathways in relation to the absence of expected reinforcement. Specifically, the investigators study the memory representations in fruit flies when an expected consequence of a conditioned stimulus fails to occur. Through a series of experiments, they test the prediction that in Drosophila when a conditioned stimulus is associated with a failed expectation of an appetitive food reinforcement, the conditioned stimulus will acquire aversive value, and vice versa for a failed expectation of an aversive reinforcer. The investigators combine these studies with manipulations of reinforcement pathways in the central nervous system identified and selected based on the recently released fly brain connectome. The experimental work is iteratively knitted in with established computational models.

A companion project is being funded by the French National Research Agency (ANR).

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Improved precision in measurement has enabled numerous scientific and technical breakthroughs. For example, increased resolution in timing arising from the development of ultrashort laser pulses has enabled entirely new approaches to study molecular dynamics on short time scales. This project aims at developing experimental methods for the generation, manipulation and measurement of quantum-mechanical states of light and to exploit these for quantum-enhanced sensing under adverse conditions in which optical loss and background noise are present. The project goes beyond prior work by utilizing multiple optical channels, or modes, that can have strong quantum-mechanical correlations, known as entanglement, to both enhance the precision in optical interferometry, but also suppress the contributions of background noise. To diversify, educate and train the upcoming quantum workforce the project will provide a solid background and mentoring in quantum and nonlinear optics for a postdoctoral researcher, graduate student, undergraduate students, as well as related outreach activities. <br/><br/><br/>The project will focus on the experimental development of multimode squeezed vacuum states generated by pulsed spontaneous parametric down conversion. Two different approaches to detecting the nonclassical light will be developed – a photon-number-resolving spectrometer and photon-counting sum-frequency generation. The project will explore theoretically the fundamental limits of sensing in realistic settings, where loss, noise and other imperfections arise. Photon addition and subtraction in well-defined temporal modes will be explored as means to boost the performance of quantum sensing protocols. The project results will advance the understanding of the role entanglement in sensing and influence future quantum-enhanced sensing research.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.