Kenneth Lyle Shepard - US grants

This research addresses the need to consider details of the analog behavior of digital circuits and interconnect in order to ensure correct functionality. Specifically it focuses on analysis of timing and noise in deep submicron circuit designs. All noise sources in a digital integrated circuit are being considered - coupled and ringing noise on signal lines, power supply noise, and noise from the circuits The effect of noise on delay is being considered in performance verification. Because many of the emerging timing and noise problems are associated with on-chip inductance, techniques for practically extracting on-chip inductance will be developed. The question of how the complex time-domain responses that result from inductive interconnect can be used in static timing and noise analysis is being investigated. Additional explorations are on using the complex time-domain responses that result from inductive interconnect for static timing and noise analysis. Other areas of investigation include a static solution to on-chip power grid integrity analysis and noise considerations in synthesis and circuit tuning. The educational plan includes building a VLSI CAD research laboratory, and development of courses in hardware design using FPGAs.

The 1990's have witnessed explosive, if not revolutionary, growth in wireless telecommunications, fueled in large measure by the technology scaling of digital processing power. Third-generation (3G) wire-less systems promise even more with high-bit-rate data services, such as video and Internet access, with wide-band spread-spectrum modulation. Yet, despite the continued benefit of technology scaling below
0.1am in the next decade, these mobile 3G systems will demand digital processing power, along with programmability and energy efficiency, which are not achievable with conventional digital design techniques. Reconfigurable and flexible software radios, which implement digital IF as well as baseband function, will be essential for 3G systems because of the need to support multiple modulation waveforms and multiple air interface standards. These systems can be expected to demand 1000 MIPS of digital IF-processing
power and up to 2000 MIPS of baseband DSP power. To achieve power levels necessary for mobile sys-tem, energy efficiency of better than 0.15 mW/MIPS while deliever 3000 MIPS of processing power will be necessary, an order of magnitude better than what can be achieve today with conventional design practices. In this extensive three-year research effort, we will consider asynchronous design techniques for achieving
energy-efficient, high-performance digital signal processing for 3G wireless applications. We will fully exploit the inherent high-performance and low-power properties of asynchronous design, to consume power only where needed and to "adapt" to the actual data inputs. Specifically, we will combine fine-grained asynchronous micropipelines with adaptive (or programmable) power-supply control and a dataflow-driven microarchitecture to provide a funcadmental leap in complex programmable digital
signal processing power and energy efficiency, unachievable using existing synchronous techniques. We in-tend to develop an asynchronous programmable DSP that is capable of supporting a significant fraction of the IS-95 and W-CDMA standards in software, including the performance- and power-intensive I and Q modulation and demodulation at less than 400 mW of peak power dissipation.

0428544
Shepard
This research addresses the development of multiplexed CMOS-based fluorescence sensors for sensing biomolecules (proteins and DNA). The goal is to develop generalized planar arrays with sensor densities on the order of ten thousand sensors per cm2. The investigators will explore both steady state and dynamic fluorescence. The sensor will contain an integrated interference filter consisting of quarter-wavelength layers for rejecting the excitation source. The investigators will consider many measurement issues, and are guided in part by their previous experience with the CMOS biochip labeled Imager F1. These issues include leveraging of economies of scale to provide low-cost devices; optimizing device self-sufficiency and miniaturization to afford maximum portability; developing parallelized designs for detection of multiple target analytes; enabling sensor-level logic for detection, calibration, and control; and optimizing dynamic range, sensitivity, and speed of detection. The existing technology is to do the detection chemistry on a glass slide, and then to carry out the detection via external sensors (or readers). This design while robust is meant for a laboratory setting. The proposed approach of integrating sensing chemistry with sensors has the potential of being compact and portable.

Proposal no: 508319
Title: NER/SNB: High-frequency, three-dimensional integrated CNFET/CMOS technology
Inst: Columbia University
PI: Ken Shepard


Carbon nano-tube field-effect transistors (CNFET) have emerged as a potential alternative field-effect technology to conventional deep-submicron silicon transistors. While operating under physical principles similar to complementary metal-oxide semiconductor (CMOS) silicon field-effect transistors, these devices offer several possible advantages in circuits including reduced short-channel effects, potential molecular-level control to reduce variability, and a hybrid three-dimensional integration in which active devices (CMOS on the bottom and CNFET on the top) will sandwich the metal interconnect layers. For any of these potential advantages to be realized, these devices must coexist with silicon CMOS FETs and must be able to leverage the existing investment in CMOS process technology. By combining CMOS-compatible CNFET fabrication with comprehensive circuit-focused device characterization, the PIs seek to further explore the potential advantage of CNFETs for real microelectronics applications while pursuing the development of viable circuits that combine CNFET transistors with conventional deep submicron CMOS technology.

Proposal no: 0541278.
Luca Carloni
Kenneth Shepard (co-PI)
Columbia University

Title: CMOS VLSI Design of Low-Power Scalable Heterogeneous Networks for Multi-Core Systems-on-Chip.

During the past decade, interconnects have replaced transistors as the dominant determiner of integrated circuit performance by imposing primary limits on latency, energy dissipation, signal integrity and design productivity for giga-scale integration. Low-latency, low-energy circuits for communications will require regular, structured interconnect to engineer wires and tune circuits to those wires. On-chip networks (OCN)
provide such a structured fabric in which communication is obtained by routing packets through a general-purpose interconnect structure rather than using a design-specific ad hoc global wiring network routed by CAD tools. The PIs will investigate the design of scalable OCNs for multi-core systems-on-chip by combining a new low-latency, low-energy, current-mode signalling approach based on damping
compensation with the design of latency-insensitive communication protocols extended to support fault-tolerant communication as well as dynamic voltage and frequency scaling and power-down for the cores.

DESCRIPTION (provided by applicant): The proposed effort combines air sampling devices and highly-integrated protein microarrays to permit estimation of multiple protein allergen exposures in a time efficient manner. Portable air sampling devices that fit inside the nostrils and have been used in Australian and European asthma studies will be used for collection of samples in an ongoing study of inner-city New York homes of children (n=200) with increased risk for developing allergy and asthma. Highly multiplexed protein microarrays, allowing parallel assessment of many allergens, integrated onto active complementary metal-oxide-semiconductor (CMOS) substrates will be employed. The use of CMOS allows highly integrated and sensitive devices to be developed because of the immediate proximity of the detector to the sensing electronics. As the commodity technology for microelectronics, such active substrates can be produced at very low cost. An established fluorescence based sensor substrate will be employed for initial studies, augmented by simple microfluidic delivery. Biosensor technology development will include efforts toward real-time measurement capabilities including more complex microfluidic delivery (including pressure activated valves), real-time fluorescence sensing through lifetime-sensitive FRET, and CMOS-integrated mass-based biosensors. The same principles for assessment of allergens in air can be applied to assessment of bacterial and fungal pathogens and their constitutive toxins. These studies have far-reaching implications for acute and chronic measures of public health.

NIRT: Molecular electronic devices with carbon-based electrodes on active substrates
Colin Nuckolls, Department of Chemistry, Columbia University
Kenneth Shepard, Department of Electrical Engineering, Columbia University
Philip Kim, Department of Physics, Columbia University
Qiao Lin, Department of Mechanical Engineering, Columbia University
Matthew Francis, Department of Chemistry, University of California Berkeley

The objective of this research is to develop a new class of nanoscale biosensors based on molecular electronic devices that utilize carbon nanotube and graphene-based electrodes. The approach centers around using chemistry to incorporate biological macromolecules as recognition domains on molecular bridges and to further develop these molecular-electronic devices as sensors. These biosensors will be fabricated on active complementary metal-oxide-semiconductor microelectronic substrates to provide true single-molecular sensitivities with potentially submicrosecond temporal resolution.
The intellectual merit of the proposed effort is centered on the sensitivity and specificity that can be achieved using this approach. Because these sensors do not rely on temporal or ensemble averaging to achieve sensitivity, they monitor individual events at a true single-molecule level, providing measurement of rich stochastic dynamics of probe-target interactions. In particular, the research effort involves new scientific investigations involving nucleic acid hybridization, protein-protein interactions, and protein conformation changes with single-molecule sensitivity, yielding new insight into processes such as folding and catalysis. These highly integrated devices will have broad practical application in medical diagnostics (genomics and proteomics), drug discovery, and environmental monitoring.
This integrated program of research and education has broad impact in training graduate and undergraduate students in a cross-disciplinary research environment. The research has broad impact to a range of science and technology including medicine, pharmacology, semiconductors, homeland security, and environmental monitoring. Significant effort will be made for K-12 outreach by systematically training highly motivated high school students within the program and also enhancing the interaction with local K-12 educators.

Progress in the biological sciences and medicine relies increasingly on methods, approaches, and strategies derived from synergistic interactions with the physical sciences and engineering. One notable example of this is the use of optical methods for biosensing and bioimaging. Furthermore, the tremendous nanoscale device fabrication capabilities built up in microelectronics and photonics furnish unparalleled opportunities for leveraging highly integrated platforms for on-chip biological sensor systems. By their nature, these applications cross through multiple disciplines and require a team with diverse expertise in the fundamental light/tissue interaction, complex optical instrumentation and imaging tools, and relevant biological systems. In this Integrative Graduate Education and Research Training (IGERT) program a new generation of scientists and engineers will be trained through a set of five research thrusts that cross three fundamental core competency areas: optics, photonics, and sensor electronics; biomolecular detection and cellular-level analysis; and applications to medicine and public health. Each IGERT trainee will be empowered to work at the boundaries between the disciplines and will be uniquely capable of contributing to advancements in this important emerging field. With 19 faculty members representing academic departments across Columbia University's School of Engineering and Applied Science, School of Arts and Sciences, Mailman School of Public Health, College of Physicians and Surgeons, and Teachers College, and incorporating strong interaction with City College, Queens College, and The Cooper Union in New York City, the IGERT trainees will experience a truly diverse community sharing in the integrated educational and research activities and will be exposed to a wide spectrum of cutting-edge applications. An external advisory board including industrial and government labs will provide additional connections between the IGERT and outside partners. Educationally, this IGERT program fulfills a compelling need to train a diverse workforce of U. S. scientists and engineers trained in an area of large and growing competitive importance to the United States. The proposed enrichment program provides IGERT fellows with enhanced training through experience in industry and government laboratories, seminars on professional development, career guidance, entrepreneurship, and discussion of ethical issues. Significant resources are committed to ensuring recruitment and retention of fellows from underrepresented groups. IGERT is an NSF-wide program intended to meet the challenges of educating U.S. Ph.D. scientists and engineers with the interdisciplinary background, deep knowledge in a chosen discipline, and the technical, professional, and personal skills needed for the career demands of the future. The program is intended to catalyze a cultural change in graduate education by establishing innovative new models for graduate education and training in a fertile environment for collaborative research that transcends traditional disciplinary boundaries.

The objective of this research is to develop a new class of on-chip power electronics circuits that will enable highly granular, active power management for future multicore processors, allowing energy-delay trade-offs to be performed in the presence of workload variability. The approach is based on the introduction of magnetic materials as a "post-process" on a standard CMOS run.

Intellectual Merit. Current implementations employ off-chip, board-level voltage regulation and bring in independent supply voltages from off-chip. Such approaches are not scalable and require that power be delivered to the chip at highly scaled voltage levels, leading to unsustainable current demands. We specifically address how passive magnetic devices can dramatically improve the design of on-chip power management and delivery circuits by providing for high density energy storage on-chip. We will innovate new magnetic devices (inductors and GMR sensors) that can be implemented on a conventional CMOS process.

Broader Impacts. This project will allow the PIs to train graduate and undergraduate students in a truly cross-disciplinary research environment combining physics, nanoscale materials, circuit design, and power electronics applications. This research effort will also feed a new course at Columbia on power electronics, with a special emphasis on integrated approaches, bridging the disconnect between the power electronics community and the traditional integrated circuit design community. Significant effort will be made for K-12 outreach by systematically training highly motivated high school students within the program and also enhancing the interaction with the local K-12 educators.

While the continued scaling of transistor dimensions enables the integration of an increasing number of processing cores on a single chip, the performance of future multicore processors will be limited by power dissipation and peak temperature constraints. High-performance computing systems will be achievable only through energy-efficient design and energy-aware programming methods. Each core will require dedicated active power and frequency management to make sure that at any given instant it does not waste any energy by operating at a speed higher than what is required by the given task that is executing. Such management requires the introduction of novel on-chip voltage regulation modules, real-time monitoring of the current usage for each voltage domain, as well as detailed awareness of the extent of parallelism achievable for each running application.

The PIs will investigate the design and fabrication of a scalable on-chip infrastructure for message-passing multicore processors that integrates support for efficient inter-core communication with programmable fine-grain control mechanisms to regulate independently the processing speed and power dissipation of each core. The proposed infrastructure will consist of a heterogeneous network-on-chip (NoC), a set of voltage and frequency control modules that are distributed on the chip, each next to the controlled core, and a new application programming interface (API). The NoC will be dynamically configured to sustain multiple traffic classes with different quality-of-service requirements. The fine-grained power management will rely on high-Q on-chip magnetic energy storage through the use of magnetic materials in a CMOS post-process fabrication step combined with high-efficiency Buck converters based on pulse-width modulation with hysteric control for fast response times. The API will expose both the inter-core message-passing communication and the voltage/frequency control of each core to the application software programmers.

This proposal will allow the PIs to train graduate and undergraduate students in integrated circuit design employing a leading edge CMOS technology and exploiting new magnetic materials as well as in hardware/software co-design of on-chip infrastructures for dynamic power management. Ongoing industrial interactions with leading information-technology and semiconductor companies promise continual relevance of the project and avenues for dissemination.

IDBR: CMOS cameras for high-frame-rate time-correlated single-photon counting

Recent advances in biological imaging techniques, particularly those exploring molecular dynamics, are outpacing technological innovation. Fluorescence lifetime holds great potential as a biomarker that can reveal changes in a fluorophore's local chemical and physical environment, as well as the binding dynamics of single proteins through excited state interactions and Förster resonance energy transfer (FRET). Many of the latest active dyes, molecular probes and even transgenic labeling strategies exploit FRET to enable real-time observation of cellular processes both in-vitro and in-vivo. While FRET can be detected using intensity-only measurements, quantitation can be dramatically impaired by experimental factors such as photobleaching, whereas lifetime-based FRET measurements are significantly more robust. Nevertheless, adoption and widespread use of fluorescence lifetime imaging microscopy (FLIM) for biological research has been hindered by two major factors: the speed with which FLIM images can be acquired and the cost and complexity of the instrumentation required for FLIM. In this multidisciplinary proposal, a novel two-dimensional high-frame-rate complementary metal-oxide-semiconductor (CMOS) fluorescent lifetime camera chip based on single-photon avalanche diodes (SPADs) will be developed. This chip will be applied to both wide-field and laser-scanning-based microscopy techniques to enable several important advances in FLIM imaging. In widefield imaging, this will result in acquisition of images at a incident-photon-limited frame rate as high as 1 kHz.

Solid-state imagers are based primarily on two technologies, charged-coupled device (CCD) and CMOS. Both of these imaging technologies are based on converting photons to electrons and collecting many of these electrons to produce a measurable signal. These imagers are now employed in digital cameras of every type, from cell phone cameras to the high-end cameras employed in biological imaging. Since optical techniques are so pervasive in probing biological systems, cameras represent the fundamental interface between the biological world and the solid-state world. In this effort, an entirely new camera chip will be designed based on a device that, instead of collecting electrons produced by photons, counts them, one-by-one. This enables very high sensitivity for photon detection. At the same time it allows resolution of very short (and dim) optical events (on the order of 10's of ps). Such capabilities will enable new types of biological imaging applications. This project supports the multidisciplinary training of graduate and undergraduate students and a significant K-12 outreach effort.

The High Frame Rate Fluorescence Lifetime Imaging Microscopy system promises new fluorescence imaging capabilities at costs dramatically lower than current systems. By integrating detectors and converters on a single platform, frame rates in excess of 100 frames/second at a production cost of under $1000 should be possible. This compares with image acquisition times of a few seconds per frame at near 100 times the cost fopr currently-available systems.

This proposal will assist the team in assessing the commercial viability of the research that was previously sponsored by NSF. If successfully commercialized, the team will deliver a new technology that advances the state of the art in fluorescence lifetime imaging microscopy. This advancement will allow measurements of dynamics of fluorescence lifetimes with an inexpensive and simple system. These measurements could lead to further advances in microscopy as well as the development of new medical diagnostic systems. In addition to the scientific advances that would be possible with widespread adoption of the system, there would also be positive economic impacts that would result from transitioning the hardware from the lab and ramping production.

The objective of this research is to develop a fully-integrated complementary metal-oxide-semiconductor (CMOS)-based platform for terahertz spectroscopy of bio-molecules. The approach is the development of widely-tunable high-power terahertz signal sources based on device stacking and multi-mode phenomena, coherent terahertz sub-harmonic mixer-based detectors and planar passive transmission-line-based terahertz resonator transducers and associated micro-fluidics for bio-molecular analysis.
The intellectual merit of this research lies in the development of new design techniques for terahertz circuits that operate beyond the cutoff frequency of the devices used, and overcome the challenges posed by scaled silicon technologies for terahertz power generation, including low breakdown voltage and high active and passive device loss. Additionally, new concepts will be developed for the interfacing of silicon-based electronics with biological material.
The broader impact of the proposed research is its ability to open up new applications for silicon electronics. Silicon electronics lies at the heart of the digital and communication revolutions. The terahertz frequency range offers new applications that could significantly impact quality of life much in the way the digital and communication revolutions have, including low-cost hand-held medical imaging, bio-spectroscopy for bio-molecular recognition and disease diagnosis, and extremely-high-data-rate communication to name a few. The proposed research also furthers efforts to interface silicon electronics with wet biological material, which will impact other applications of silicon electronics in the life sciences. This proposal will allow the investigators to train graduate and undergraduate students in a cross-disciplinary research environment combining physics, nano-scale materials and fabrication, circuit design, and biology applications. Significant effort will be made for K-12 outreach by systematically training highly motivated high school students within the program and also enhancing the interaction with the local K-12 educators through interaction with the Double Discovery Program and the Columbia University Science Research Program.

Over the last two decades, fluorescent techniques have become the standard method for experimentally probing the conformational dynamics of molecules at the single-molecule level both in vitro and in vivo. Though fluorescent probes are highly specific, they use light as an intermediary between the biological system and measurement electronics, which results in fundamental constraints in resolution and bandwidth due to the countable number of photons emitted. Single-molecule kinetic measurements of fast biomolecular processes are often difficult or impossible to access through fluorescent techniques, as they lack the necessary temporal resolution. Long time scales are frequently also difficult and sometimes impossible to access due to fluorophore photobleaching.

In this multidisciplinary project, charge-based field-effect-transistor (FET) electronic single-molecule methods are developed for the analysis of biomolecular interactions in in vitro biomolecular systems. These techniques will dramatically improve the temporal dynamic range for single-molecule studies, enabling bandwidths approaching 10 MHz as well as the ability to examine single-molecule events over hours of observation time. Integration of these electronic sensors with complementary metal-oxide-semiconductor (CMOS) integrated circuits will enable the high throughput techniques that currently characterize many current, fluorescence-based approaches. This project focusses on two specific single-molecule studies involving nucleic acid and protein interactions which demonstrate the benefits of improved temporal resolution. State-of-the-art single-molecule techniques have been actively employed to study these systems; as a result, they represent an interesting vehicle to apply the FET devices proposed here.

Intellectual Merit:
This research program seeks to combine these efforts and is centered around four specific research aims: (1) optimization of field-effect-transistor (FET) devices for high-bandwidth single-molecule sensing; (2) CMOS integration of these field-effect sensors into a large multiplexed platform; (3) single-molecule FET studies of riboswitch folding and function; and (4) single-molecule studies of the dynamics of lactose repressor protein interacting with DNA. Specifically, in the first two Aims, we develop a nanoscale FET platform for single-molecule detection, enabling bandwidths approaching 10 MHz with massively parallel, high-bandwidth integrated CMOS electronics as well as the ability to examine single-molecule events over hours of observation time. The second two Aims focus on target application of these sensors in the study of nucleic acids and proteins.

Broader Impacts:
In this project, the PIs will train graduate and undergraduate students in a truly cross-disciplinary research environment combining biochemistry, nanofabrication, circuit design, and biological applications. The proposed program will also impact curricula, as described below, allowing us to influence a broader group of students. Based on an established track record of the PIs, significant effort will be made for K-12 outreach by systematically training highly motivated high school students within the program and also enhancing the interactions with local K-12 educators to introduce front-line research to students, especially targeting underrepresented groups. We also intend broader impacts related to the commercialization and dissemination of this proposal?s technology.

Directional dry etching constitutes a fundamental fabrication technique in the research and manufacturing of micro- and nanoscale devices. The proposal seeks funding to allow Columbia University to acquire an advanced etching system that allows for a diverse set of uses and will expand the range of a variety of current projects at Columbia, including projects related to nano-electronics, nanobiology and nano-neuro-biology, optoelectronics, photovoltaics and medical research. The equipment will also enable a range of future projects that are currently not possible, including lasers at the nanoscale level and a class of semiconductors known as III/V semiconductors. As a major upgrade to the shared Columbia Cleanroom -- currently the only shared cleanroom facility in the New York City metropolitan area --the etching system to be acquired will directly impact the educational and research activities of over 250 researchers (faculty, staff, and students) at Columbia and neighboring institutions. The group of co-Principal Investigators includes all the researchers who serve on the Cleanroom Board of Directors, representing an accumulation of experience in the successful installation and support of such equipment for a varied and evolving set of users. The facility also hosts graduate and undergraduate lecture and laboratory courses taught by the co-PIs, REUs and RETs, and independent study projects advised by faculty from many departments. Since nanopatterning is a central component of these courses, the requested etcher will directly impact the educational program of several departments, providing students with important skills for future careers in science and engineering.

The ICP RIE (inductively-coupled plasma, reactive ion etching) system described in this proposal will employ chlorine-based etch chemistries for vertical etching of compound semiconductors, metals, and organic materials. The new patterning capability and system will enable a range of future projects including nanoscale lasers and sensors based on III/V semiconductors. During operation of the etcher, recipes will be systematically developed to provide optimal results to all researchers. The Columbia University clean room is currently the only shared-access micro- and nano-fabrication facility in the metropolitan New York City area and serves a diverse population of academic users and small businesses. The facility has permanent technical and administrative support, and the proposed ICP RIE system will constitute a crucial facility of the available infrastructure for research training in nanoscale science and engineering. The tool will be used directly by students and post-doctoral researchers as part of their research activities, providing training in advanced nanopatterning techniques.

Clinical presentation, particularly early in the course of disease, is only rarely pathognomonic of infection with a specific infectious agent. As a result, diagnosis is complex with many different organisms causing similar symptoms. Given that effective intervention requires accurate diagnosis and that the probability of success diminishes over time, tests that enable rapid, efficient differential diagnosis have potential to decrease morbidity, mortality, and social and economic costs of infectious diseases. Polymerase chain reaction (PCR) is not well suited to highly multiplexed microbiological analyses because primer interactions can reduce sensitivity and the repertoire of reporter systems is typically limited to 10 to 20 targets. DNA microarrays allow extensive multiplexing but existing assays are less sensitive than agent-specific PCR and require amplification, fluorescent labeling and several hours for processing. Next generation sequencing has unlimited multiplex potential. However, current platforms require hours to days for sample processing and bioinformatic analysis and are too complex for most point-of-care applications. In this project we will develop a single-molecule field-effect transistor (smFET) diagnostic assay platform. This application draws on our recent work, in which we have shown that the conductance of a carbon nanotube with a single covalently tethered DNA probe molecule is exquisitely sensitive to the increased charge that results from hybridization of a complementary DNA strand. smFET arrays on active complementary metal-oxide-semiconductor (CMOS) substrates will allow genomic materials to be assayed to concentrations approaching 1 fM (or 600 molecule per mL), comparable to qPCR, but while allowing multiplexing comparable to microarrays. We will specifically apply this technology to a genomic diagnostic platform that will allow efficient, low-cost differential diagnosis of infectious diseases. Our objectives we will be to optimize and develop the sensor to detect target concentration as low as 1 fM and develop approaches to distinguish mismatches through analysis of binding kinetics; integrate these devices onto CMOS measurement substrates, further improving electronic performance and allowing parallel multiplexing; test the platform with clinical samples in a staged strategy that begins in minimal biocontainment with nucleic acid templates, proceeds to work with potentially infectious materials in biocontainment; reduce the form factor for the device to that of a portable USB stick; and build software and bioinformatics infrastructure to support this platform for deployment in the field and clinics.

An award is made to Columbia University to develop an electrochemical imager chip (EIC) whose purpose it is to study redox-active molecules in microbial biofilms. The EIC platform will have broad significance in understanding biofilm formation and may be used to interfere with biofilm development. In natural, industrial, and clinical settings, the redox transformations caused by microbes in biofilms often determine the overall functionality of an ecosystem and its environmental impact. Examples include sulfur compound transformations catalyzed by bacteria in salt marshes, microbially induced corrosion of oil pipelines, and the fermentative metabolisms of communities in the digestive tract. Furthermore, biofilm formation is a critical step in the establishment of many different types of infections and one that enhances antibiotic resistance, exacerbating the challenge of treating such infections. This research will also support education and outreach efforts by incorporating this instrument into a new course on bacterial physiology and biofilm formation, sponsorship of summer research by undergraduates, and a K-12 outreach program.

The most complex engineered systems to-date are integrated circuits (IC) exploiting silicon complementary metal-oxide-semiconductor (CMOS) technology, which has spawned a global technology revolution in computing and communications applications. In this project, we will use CMOS IC technology to create a new type of instrument capable of high spatial- and temporal-resolution electrochemical imaging of planar multicellular structures that are placed in contact with the chip. In particular, we will study (1) phenazines, a class of redox-active antibiotics produced by Pseudomonas aeruginosa biofilms, which vary in structure and chemical properties and have individualized, drastic effects on community morphogenesis; and (2) nitric oxide (NO), an intermediate in P. aeruginosa denitrification, a metabolic process that also affects colony morphogenesis when nitrate is made available in the environment. NO has been implicated in multicellular behavior and development in diverse organisms.

This award is being made jointly by two Programs- (1) Instrument Development for Biological Research, in the Division of Biological Infrastructure (Biological Sciences Directorate), and (2) the Biotechnology, Biochemical, and Biomass Engineering Program, Division of Chemical, Bioengineering, Environmental and Transport Systems (Engineeing Directorate).

Understanding how the brain works is arguably one of the most significant scientific challenges of our time and the focus of the BRAIN initiative. It is widely believed that neural circuit function is emergent, the result of complex interactions between constituents with individual neurons forming synaptic connections with thousands of other neurons. Mapping of these complex circuits has been virtually impossible because of the reliance on electrophysiological recordings which sample these networks extremely sparsely. These tools for extracellular spike recordings are only able to simultaneously record from several tens to a few hundred neurons. Raw signals from these recording electrodes are first filtered to remove out-of-band signals. Putative spike events are then detected and extracted. Finally, these snippets of time-series event are sorted, typically on the basis of waveform shapes, into clusters. Even at the very modest bandwidths for these systems, computing systems struggle to save the data and process the resulting data sets. Scalability of these measurement techniques by many orders of magnitude in recording density and channels will be essential to future progress in understanding neuron circuits.

This project is exploiting emerging electrophysiological recording systems in which the electrode (and channel) count is increased by almost three orders of magnitude over conventional systems with data bandwidths exceeding 1GB/sec. To handle these data bandwidths and resulting data volumes and deliver scalability, this project will develop dedicated hardware and associated algorithms for spike detection and sorting that allow these tasks to be performed in real-time in close proximity to the recording system. Compression by more than three orders of magnitude is possible by these means by taking advantage of the special spatiotemporal local structure in these data sets; by exploiting strong prior information about the spiking signal and reducing the dimensionality of the problem accordingly; and by adapting and extending modern scalable nonparametric Bayesian inference methods. In addition to providing important new tools for neuroscience, the tools developed here for scalable real-time event detection and annotation have broad applicability to other spatiotemporal data sets (or more generally, any data set comprising multiple streams of data, in which the streams could involve different data modalities) in which objects of interest are spatially and temporally localized with fixed spatial footprints. Examples abound in cell and molecular biology, particle and solid-state physics, financial monitoring, monitoring of power networks, and sensor networks.

Abstract In this proposal, we will develop next-generation flexible micro-electrocortigraphic (µECoG) and penetrating electrode arrays using active electronics in complementary metal-oxide-semiconductor (CMOS) technology. Active electronics enable amplification and multiplexing directly at each electrode, eliminating the need for implanted electrodes to be individually wired to remote electronics and greatly increasing the number and density of electrodes that can be recorded and stimulated. The flexibility of our arrays allows them to conform to the irregular geometry of the brain, yielding higher fidelity signals and reduces damage to the brain when used in penetrating configurations. Integrated wireless data and power enables completely tether-free implants. Together, these innovations enable us to take high resolution measurements over large areas of the brain while being less invasive, a substantial improvement over the current state-of-the-art. In surface recording structures, we will demonstrate electrode arrays of up to 65,536 electrodes and amplifiers, spaced just 25.4µm apart, where each electrode can be simultaneously sampled at 20 ksps, enabling a cellular-resolution brain interface across a 64 mm² brain area. Each electrode can also be independently stimulated, or stimulated with patterns of activation, mimicking more natural excitation patterns. In penetrating arrays, we will demonstrate fully integrated, flexible penetrating neural probes with up to 512 electrodes per shank. The probe ?head? containing active electronics will fold over the outer surface of the cortex, at the point of the probe?s insertion, positioning its inductor for a near-field link through the skull. This link will be powered wirelessly with near-field radio-frequency data telemetry, eliminating the need to run wired interconnections through the skull. Integration with wireless interfaces will permit sealing chronically- implantable probes subcutaneously and in a manner in which the entire probe floats on the brain. The developed technologies will be rigorously tested in vitro and in vivo. This project will make high density electrode arrays based on manufacturable flexible CMOS technology available for the broader neuroscience community, enabling studies of large-scale recording and modulation in the nervous system. The innovations generated through this work have the potential to revolutionize our ability to understand the brain, and will improve epilepsy surgery outcomes as well as advance the performance of motor and auditory prosthetics. This project leverages a successful, long-term collaboration between clinicians, engineers, material scientists and neuroscientists at Duke University, Columbia University, New York University and the University of Illinois at Urbana-Champaign, to translate active, flexible electronics technology into next generation implantable neurological devices.

This collaborative proposal by Dr. Shepard from Columbia University and an international team of researchers from the UK, will develop an optical imaging approach to study freely-behaving animals and potentially humans. The proposal explores original and transformative approaches for overcoming current barriers of functional imaging of the brain. If successful, the platform developed by this project will be critical to many research projects, which will further understanding of the functioning of the brain as well as various brain disease mechanisms

The approach builds on the development of a dense 3D lattice of emitters and detectors embedded onto ultra-narrow implantable neural probes. The proposal includes 3 aims comprising (1) the development of fully integrated high-density optogenetic stimulators, (2) development of time-gated fluorescence detection of lens-free neuronal recordings and (3) in vitro and in vivo characterization and validation of the system. The work includes educational and outreach activities, including; integration of educational material into courses on neuroscience, bioelectronics and biophotonics at Columbia University and at St. Andrews.

Viral infections in the last decades with different strains of the coronavirus (CoV) have led to the SARS-CoV (2003) and MERS (2012) epidemics and to the most recent COVID-19 pandemic (2019). At this point, no vaccine or effective antiviral drug is commercially available for these human pathogens. CoVs are built out of four major structural proteins; the nucleocapsid (N) protein engulfing the viral RNA, the spike (S) protein, the membrane (M) protein and the envelope (E) protein. Presently, academic and pharmaceutical efforts are mainly focused on the S-protein which is involved in the entry of the virus into the host cell, whereas the M- and E-proteins are less well studied but are shown to be involved in viral replication. This project will study the E-protein from different CoV strains to better understand its function. This project will improve our understanding of SARS-CoV-2, and this understanding is knowledge necessary to identify new therapeutics to control this current COVI-19 pandemic. In addition to increasing knowledge about SARS-CoV-2 biology, this project also supports the training of a post-doctoral fellow, broadening participation in STEM.

This project will study the E-protein of SARS-CoV-2 and other coronaviruses (CoVs) to understand the role of this ion channel in host-virion interaction. A multi-level approach will be used to gain comprehensive understanding on effects of the post-translational modifications and sequence variability of various E-proteins from different CoV strains. Patterns in the post-translational modification of E-proteins will be identified to determine whether these modifications affect the functionality of the E-protein in model membranes. Using model membranes allows for control of key-features in the membrane environment, namely charge of lipid head-groups and saturation of fatty acids creating a microdomain or non-microdomain environment. The throughput of these recordings will be increased by using our unique abilities to combine modern electronics and membrane biophysics. E-proteins from different CoV strains will be used to identify the impact on the development of productive or non-productive infections in a host-like environment. The current COVID-19 public health emergency makes understanding this new pathogen of urgent importance. Little is known about this novel CoV and its relationship to other CoV virions. Understanding better the exact role that the E-protein plays in the host-virion interaction will be very helpful in devising new therapeutics. This RAPID award is made by the Physiological and Structural Systems Cluster in the BIO Division of Integrative Organismal Systems, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.

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.

Project summary The research proposed in this application is designed to elucidate the structure-function relationships of a form of exercise-induced sudden death known as catecholaminergic polymorphic ventricular tachycardia (CPVT), caused by mutations in the Type-2 ryanodine receptor (RyR2)/calcium release channel. RyR2 channels are required for the release of calcium (Ca2+) from intracellular stores, a process that triggers cellular functions including excitation-contraction (EC) coupling in the cardiac muscle. RyR2, along with RyR1 and RyR3, are the largest known ion channels, comprised of the four identical ~565 kDa channel-forming protomers, as well as regulatory subunits, enzymes, and their respective targeting/anchoring proteins in a macromolecular complex that exceeds three million daltons. It is known that RyR2 mutations cause arrhythmias including exercise-induced sudden death, or CPVT, and stress- induced post-translational modifications of RyR2 contribute to both CPVT and heart failure progression. The applicants have recently obtained near-atomic-level resolution cryo-electron microscopy (cryo-EM) reconstructions of Type-1 RyR (RyR1) from highly purified rabbit skeletal muscle in both the closed and the open states, defining the transmembrane pore in unprecedented detail and placing all cytosolic domains as tertiary folds, including a Ca2+ domain. Using modeling software, the structure of RyR2 has been modeled based on homology with RyR1. We propose to study the localization, structural effects, and function of at least 11 representative pathogenic CPVT mutations, in order to develop a system for understanding how pathogenic genetic variants in different regions of the channel cause clinical disease. These studies will be conducted by solving cryo-EM structures of mutant RyR2 channels and by functionally testing these mutations using a novel, high bandwidth, high-throughput lipid bilayer technology developed by our team. This technology is capable of identifying channel opening events with nanosecond resolution (compared to current single channel current resolution of millisecond resolution). We will then develop a database of all known genetic variants CPVT-associated and systematically engineer these mutations into recombinant RyR2 in order to study these channels using our novel high-throughput lipid bilayer measurement system. The data from this project will be useful for understanding the underlying mechanisms of CPVT. It will provide an approach that can be used to develop therapies for CPVT. It will advance our understanding of novel technologies for studying other diseases caused by RyR2 dysfunction and for studying other ion channels.