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Filament-Free Bulk Resistive Memory Enables Deterministic Analogue Switching

Advanced Materials

Li, Yiyang; Fuller, Elliot J.; Sugar, Joshua D.; Yoo, Sangmin; Ashby, David; Bennett, Christopher H.; Horton, Robert D.; Bartsch, Michael B.; Marinella, Matthew J.; Lu, Wei D.; Talin, A.A.

Digital computing is nearing its physical limits as computing needs and energy consumption rapidly increase. Analogue-memory-based neuromorphic computing can be orders of magnitude more energy efficient at data-intensive tasks like deep neural networks, but has been limited by the inaccurate and unpredictable switching of analogue resistive memory. Filamentary resistive random access memory (RRAM) suffers from stochastic switching due to the random kinetic motion of discrete defects in the nanometer-sized filament. In this work, this stochasticity is overcome by incorporating a solid electrolyte interlayer, in this case, yttria-stabilized zirconia (YSZ), toward eliminating filaments. Filament-free, bulk-RRAM cells instead store analogue states using the bulk point defect concentration, yielding predictable switching because the statistical ensemble behavior of oxygen vacancy defects is deterministic even when individual defects are stochastic. Both experiments and modeling show bulk-RRAM devices using TiO2-X switching layers and YSZ electrolytes yield deterministic and linear analogue switching for efficient inference and training. Bulk-RRAM solves many outstanding issues with memristor unpredictability that have inhibited commercialization, and can, therefore, enable unprecedented new applications for energy-efficient neuromorphic computing. Beyond RRAM, this work shows how harnessing bulk point defects in ionic materials can be used to engineer deterministic nanoelectronic materials and devices.

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Library preparation for the Oxford Minion sequencer with 'ASPIRE': Automated sample PrEP by indexed rotary exchange

21st International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2017

Jayamohan, Harikrishnan J.; Sinha, Anupama S.; Krishnakumar, Raga K.; Edwards, Harrison E.; Younis, Tariq A.; Trevithick, Jacob D.; Patel, Kamlesh P.; Bartsch, Michael B.

We report a prototype system to automate the DNA library preparation of bacterial genomes for analysis with the Oxford MinION nanopore sequencer as a first step towards a universal bacterial pathogen identification and biosurveillance tool. The ASPIRE (Automated Sample Preparation by Indexed Rotary Exchange) platform incorporates a rotary hydrophobic substrate that provides sequential delivery of sample and reagent droplets to heater and magnetic bead trapping modules via a single capillary coupled to a syringe pump. We have applied ASPIRE-based library preparation to lambda-phage and E. coli genomic DNA (gDNA) and verified its ability to produce libraries with DNA yield and ultimate sequenced read size distribution, quality, and reference-mapping percentages comparable to those obtained for benchtop prep methods.

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Systematic and stochastic influences on the performance of the MinION nanopore sequencer across a range of nucleotide bias

Scientific Reports

Krishnakumar, Raga K.; Sinha, Anupama S.; Bird, Sara W.; Jayamohan, Harikrishnan; Edwards, Harrison S.; Schoeniger, Joseph S.; Patel, Kamlesh P.; Branda, Steven B.; Bartsch, Michael B.

Emerging sequencing technologies are allowing us to characterize environmental, clinical and laboratory samples with increasing speed and detail, including real-time analysis and interpretation of data. One example of this is being able to rapidly and accurately detect a wide range of pathogenic organisms, both in the clinic and the field. Genomes can have radically different GC content however, such that accurate sequence analysis can be challenging depending upon the technology used. Here, we have characterized the performance of the Oxford MinION nanopore sequencer for detection and evaluation of organisms with a range of genomic nucleotide bias. We have diagnosed the quality of base-calling across individual reads and discovered that the position within the read affects base-calling and quality scores. Finally, we have evaluated the performance of the current state-of-the-art neural network-based MinION basecaller, characterizing its behavior with respect to systemic errors as well as context- and sequence-specific errors. Overall, we present a detailed characterization the capabilities of the MinION in terms of generating high-accuracy sequence data from genomes with a wide range of nucleotide content. This study provides a framework for designing the appropriate experiments that are the likely to lead to accurate and rapid field-forward diagnostics.

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Real-Time Automated Pathogen Identification by Enhanced Ribotyping (RAPIER) LDRD Final Report

Bartsch, Michael B.; Bird, Sara W.; Branda, Steven B.; Edwards, Harrison E.; Jayamohan, Harikrishnan J.; Krishnakumar, Raga K.; Patel, Kamlesh P.; Schoeniger, Joseph S.; Sinha, Anupama S.

Funded through the IHNS/E&HS investment area for FY16-18, the RAPIER LDRD sought to evaluate the potential benefits and applicability of the new Oxford MinION nanopore sequencer to pathogen diagnostic applications in biodefense, biosurveillance, and global/public health. The project had four primary objectives: 1) to investigate the performance of the MinION sequencer while building facility with its operation, 2) to develop microfluidic library prep automation facilitating the use of the MinION in field-forward or point-of-care applications, 3) to leverage CRISPR/Cas9 technology to enable targeted identification of bacterial pathogens, and 4) to capitalize on the real- time data output capabilities of the MinION to enable rapid sequence-based diagnostics. While the rapid evolution of the MinION sequencing technology during the course of the project posed a number of challenges and required a reassessment of initial project priorities, it also provided unique opportunities, notably culminating in our development of the RUBRIC real-time selective sequencing software.

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The rotary zone thermal cycler: A low-power system enabling automated rapid PCR

PLoS ONE

Bartsch, Michael B.; Edwards, Harrison S.; Lee, Daniel; Moseley, Caroline E.; Tew, Karen E.; Renzi, Ronald F.; Van De Vreugde, James L.; Kim, Hanyoup; Knight, Daniel L.; Sinha, Anupama S.; Branda, Steven B.; Patel, Kamlesh P.

Advances in molecular biology, microfluidics, and laboratory automation continue to expand the accessibility and applicability of these methods beyond the confines of conventional, centralized laboratory facilities and into point of use roles in clinical, military, forensic, and field-deployed applications. As a result, there is a growing need to adapt the unit operations of molecular biology (e.g., aliquoting, centrifuging, mixing, and thermal cycling) to compact, portable, low-power, and automation-ready formats. Here we present one such adaptation, the rotary zone thermal cycler (RZTC), a novel wheel-based device capable of cycling up to four different fixed-temperature blocks into contact with a stationary 4-microliter capillarybound sample to realize 1-3 second transitions with steady state heater power of less than 10 W. We demonstrate the utility of the RZTC for DNA amplification as part of a highly integrated rotary zone PCR (rzPCR) system that uses low-volume valves and syringe-based fluid handling to automate sample loading and unloading, thermal cycling, and between-run cleaning functionalities in a compact, modular form factor. In addition to characterizing the performance of the RZTC and the efficacy of different online cleaning protocols, we present preliminary results for rapid single-plex PCR, multiplex short tandem repeat (STR) amplification, and second strand cDNA synthesis.

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A Microfluidic DNA Library Preparation Platform for Next-Generation Sequencing

PLoS ONE

Kim, Hanyoup; Jebrail, Mais J.; Sinha, Anupama S.; Bent, Zachary B.; Solberg, Owen D.; Williams, Kelly P.; Langevin, Stanley A.; Renzi, Ronald F.; Van De Vreugde, James L.; Meagher, Robert M.; Schoeniger, Joseph S.; Lane, Todd L.; Branda, Steven B.; Bartsch, Michael B.; Patel, Kamlesh D.

Next-generation sequencing (NGS) is emerging as a powerful tool for elucidating genetic information for a wide range of applications. Unfortunately, the surging popularity of NGS has not yet been accompanied by an improvement in automated techniques for preparing formatted sequencing libraries. To address this challenge, we have developed a prototype microfluidic system for preparing sequencer-ready DNA libraries for analysis by Illumina sequencing. Our system combines droplet-based digital microfluidic (DMF) sample handling with peripheral modules to create a fully-integrated, sample-in library-out platform. In this report, we use our automated system to prepare NGS libraries from samples of human and bacterial genomic DNA. E. coli libraries prepared on-device from 5 ng of total DNA yielded excellent sequence coverage over the entire bacterial genome, with >99% alignment to the reference genome, even genome coverage, and good quality scores. Furthermore, we produced a de novo assembly on a previously unsequenced multi-drug resistant Klebsiella pneumoniae strain BAA-2146 (KpnNDM). The new method described here is fast, robust, scalable, and automated. Our device for library preparation will assist in the integration of NGS technology into a wide variety of laboratories, including small research laboratories and clinical laboratories. © 2013 Kim et al.

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Characterization of Pathogens in Clinical Specimens via Suppression of Host Background for Efficient Second Generation Sequencing Analyses

Branda, Steven B.; Jebrail, Mais J.; Van De Vreugde, James L.; Langevin, Stanley A.; Bent, Zachary B.; Curtis, Deanna J.; Lane, Pamela L.; Carson, Bryan C.; La Bauve, Elisa L.; Patel, Kamlesh P.; Ricken, James B.; Schoeniger, Joseph S.; Solberg, Owen D.; Williams, Kelly P.; Misra, Milind; Powell, Amy J.; Pattengale, Nicholas D.; May, Elebeoba E.; Lane, Todd L.; Lindner, Duane L.; Young, Malin M.; VanderNoot, Victoria A.; Thaitrong, Numrin T.; Bartsch, Michael B.; Renzi, Ronald F.; Tran-Gyamfi, Mary B.; Meagher, Robert M.

Abstract not provided.

Copy of Automated Molecular Biology Platform Enabling Rapid & Efficient SGS Analysis of Pathogens in Clinical Samples

Branda, Steven B.; Jebrail, Mais J.; Van De Vreugde, James L.; Langevin, Stanley A.; Bent, Zachary B.; Curtis, Deanna J.; Lane, Pamela L.; Carson, Bryan C.; La Bauve, Elisa L.; Patel, Kamlesh P.; Ricken, James B.; Schoeniger, Joseph S.; Solberg, Owen D.; Williams, Kelly P.; Misra, Milind; Powell, Amy J.; Pattengale, Nicholas D.; May, Elebeoba E.; Lane, Todd L.; Lindner, Duane L.; Young, Malin M.; VanderNoot, Victoria A.; Thaitrong, Numrin T.; Bartsch, Michael B.; Renzi, Ronald F.; Tran-Gyamfi, Mary B.; Meagher, Robert M.

Abstract not provided.

Automated Molecular Biology Platform Enabling Rapid & Efficient SGS Analysis of Pathogens in Clinical Samples

Branda, Steven B.; Jebrail, Mais J.; Van De Vreugde, James L.; Langevin, Stanley A.; Bent, Zachary B.; Curtis, Deanna J.; Lane, Pamela L.; Carson, Bryan C.; La Bauve, Elisa L.; Patel, Kamlesh P.; Ricken, James B.; Schoeniger, Joseph S.; Solberg, Owen D.; Williams, Kelly P.; Misra, Milind; Powell, Amy J.; Pattengale, Nicholas D.; May, Elebeoba E.; Lane, Todd L.; Lindner, Duane L.; Young, Malin M.; VanderNoot, Victoria A.; Thaitrong, Numrin T.; Bartsch, Michael B.; Renzi, Ronald F.; Tran-Gyamfi, Mary B.; Meagher, Robert M.

Abstract not provided.

Integrated microfluidic hub for automated prepration of dna libraries for personalized sequencing systems

Proceedings of the 16th International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2012

Jebrail, Mais J.; Kim, Hanyoup; Thaitrong, Numrin T.; Bartsch, Michael B.; Renzi, Ronald F.; Patel, Kamlesh D.

While DNA sequencing technology is advancing at an unprecedented rate, sample preparation technology still relies primarily on manual bench-top processes, which often can be slow, labor-intensive, inefficient, or inconsistent. To address these disadvantages, we developed an integrated microfluidic platform for automated preparation of DNA libraries for next generation sequencing. This sample-to-answer system has great potential for rapid characterization of novel and emerging pathogens from clinical samples.

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Automated Digital Microfluidic Sample Preparation for Next-Generation DNA Sequencing

Journal of Laboratory Automation

Kim, Hanyoup; Bartsch, Michael B.; Renzi, Ronald F.; He, Jim; Van De Vreugde, James L.; Claudnic, Mark R.; Patel, Kamlesh D.

Next-generation sequencing (NGS) technology is a promising tool for identifying and characterizing unknown pathogens, but its usefulness in time-critical biodefense and public health applications is currently limited by the lack of fast, efficient, and reliable automated DNA sample preparation methods. To address this limitation, we are developing a digital microfluidic (DMF) platform to function as a fluid distribution hub, enabling the integration of multiple subsystem modules into an automated NGS library sample preparation system. A novel capillary interface enables highly repeatable transfer of liquid between the DMF device and the external fluidic modules, allowing both continuous-flow and droplet-based sample manipulations to be performed in one integrated system. Here, we highlight the utility of the DMF hub platform and capillary interface for automating two key operations in the NGS sample preparation workflow. Using an in-line contactless conductivity detector in conjunction with the capillary interface, we demonstrate closed-loop automated fraction collection of target analytes from a continuous-flow sample stream into droplets on the DMF device. Buffer exchange and sample cleanup, the most repeated steps in NGS library preparation, are also demonstrated on the DMF platform using a magnetic bead assay and achieving an average DNA recovery efficiency of 80% ± 4.8% © 2011 Society for Laboratory Automation and Screening.

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Digital microfluidic hub for automated nucleic acid sample preparation

14th International Conference on Miniaturized Systems for Chemistry and Life Sciences 2010, MicroTAS 2010

Kim, Hanyoup; Bartsch, Michael B.; Renzi, Ronald F.; Pezzola, Genevieve L.; Remillard, Erin M.; Kittlaus, Eric A.; He, Jim H.; Patel, Kamlesh D.

We have designed, fabricated, and characterized a digital microfluidic (DMF) platform to function as a central hub for interfacing multiple lab-on-a-chip sample processing modules towards automating the preparation of clinically-derived DNA samples for ultrahigh throughput sequencing (UHTS). The platform enables plug-and-play installation of a two-plate DMF device with consistent spacing, offers flexible connectivity for transferring samples between modules, and uses an intuitive programmable interface to control droplet/electrode actuations. Additionally, the hub platform uses transparent indium-tin oxide (ITO) electrodes to allow complete top and bottom optical access to the droplets on the DMF array, providing additional flexibility for various detection schemes.

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41 Results
41 Results