Limited Throughput Research Articles

A 40-nm CMOS Multifunctional Computing-in-Memory (CIM) Using Single-Ended Disturb-Free 7T 1-Kb SRAM

This investigation proposes a computing-in-memory (CIM) design to circumvent the von Neumann bottleneck which causes limited computation throughput for effective artificial intelligence (AI) applications. The proposed CIM performs multiple operations such as single-instruction basic Boolean operations, addition, and signed number multiplication, and multiple functions such as normal mode and retention mode for the built-in self-test (BIST). Its 2T-Switch requires only two transistors to be utilized for static random-access memory (SRAM) array; thus, the arithmetic unit can be chosen easily and the area overhead is minimized. Its ripple carry adder and multiplier (RCAM) unit based on single-ended disturb-free 7T 1-Kb SRAM was developed using the full swing-gate diffusion input (FS-GDI) technology that has full voltage swing resolution, low power consumption, and less chip area cost. Its Auto-Switching Write Back Circuit restores addition and multiplication operations automatically to assigned memory address. The CIM is implemented using the TSMC 40-nm CMOS process, where the core area is $432.81 \times 510.265\,\,\mu \text{m}^{2}$ . Among the related works, the proposed CIM performs the most number of operations and functions.

On the Use of Surface Plasmon Resonance-Based Biosensors for Advanced Bioprocess Monitoring

Biomanufacturers are being incited by regulatory agencies to transition from a quality by testing framework, where they extensively test their product after their production, to more of a quality by design or even quality by control framework. This requires powerful analytical tools and sensors enabling measurements of key process variables and/or product quality attributes during production, preferably in an online manner. As such, the demand for monitoring technologies is rapidly growing. In this context, we believe surface plasmon resonance (SPR)-based biosensors can play a role in enabling the development of improved bioprocess monitoring and control strategies. The SPR technique has been profusely used to probe the binding behavior of a solution species with a sensor surface-immobilized partner in an investigative context, but its ability to detect binding in real-time and without a label has been exploited for monitoring purposes and is promising for the near future. In this review, we examine applications of SPR that are or could be related to bioprocess monitoring in three spheres: biotherapeutics production monitoring, vaccine monitoring, and bacteria and contaminant detection. These applications mainly exploit SPR’s ability to measure solution species concentrations, but performing kinetic analyses is also possible and could prove useful for product quality assessments. We follow with a discussion on the limitations of SPR in a monitoring role and how recent advances in hardware and SPR response modeling could counter them. Mainly, throughput limitations can be addressed by multi-detection spot instruments, and nonspecific binding effects can be alleviated by new antifouling materials. A plethora of methods are available for cell growth and metabolism monitoring, but product monitoring is performed mainly a posteriori. SPR-based biosensors exhibit potential as product monitoring tools from early production to the end of downstream processing, paving the way for more efficient production control. However, more work needs to be done to facilitate or eliminate the need for sample preprocessing and to optimize the experimental protocols.

Microswimmers from Toposelective Nanoparticle Attachment

AbstractMicroswimmers hold promise for applications ranging from targeted delivery to enhanced mixing at the microscale. However, current fabrication techniques suffer from limited throughput and material selection. Here, a versatile route enabling the synthesis of microswimmers from off‐the‐shelf micro‐ and nano‐particles is demonstrated. The protocol hinges on the toposelective attachment of photocatalytic nanoparticles onto microparticles, exploiting a multi‐functional polymer and a Pickering‐wax emulsification step, to yield large quantities of photo‐responsive active Janus particles. The polymer presents both silane and nitrocatechol groups, binding silica microspheres to a range of metal oxide nanoparticles. The Pickering‐wax emulsions protect part of the microspheres’ surface, enabling asymmetric functionalization, as required for self‐propulsion. The resulting photocatalytic microswimmers display a characteristic orientation‐dependent 3D active motion upon ultra‐violet illumination, different from that conventionally described in the literature. By connecting the extensive library of heterogeneous nanoparticle photocatalysts with the nascent field of active matter, this versatile material platform lays the groundwork toward designer microswimmers, which can swim by catalyzing a broad range of chemical reactions with potential for future applications.

A Genome-Edited ERα-HiBiT Fusion Reporter Cell Line for the Identification of ERα Modulators Via High-Throughput Screening and CETSA.

The estrogen receptor α (ERα) is a target of intense pharmacological intervention and toxicological biomonitoring. Current methods to directly quantify cellular levels of ERα involve antibody-based assays, which are labor-intensive and of limited throughput. In this study, we generated a post-translational reporter cell line, referred to as MCF7-ERα-HiBiT, by fusing a small pro-luminescent nanoluciferase (NLuc) tag (HiBiT) to the C-terminus of endogenous ERα in MCF7 cells. The tag allows the luminescent detection and quantification of endogenous ERα protein by addition of the complementary NLuc enzyme fragment. This MCF7-ERα-HiBiT cell line was optimized for quantitative high-throughput screening (qHTS) to identify compounds that reduce ERα levels. In addition, the same cell line was optimized for a qHTS cellular thermal shift assay to identify compounds that bind and thermally stabilize ERα. Here, we interrogated the MCF7-ERα-HiBiT assay against the NCATS Pharmacological Collection (NPC) of 2,678 approved drugs and identified compounds that potently reduce and thermally stabilize ERα. Our novel post-translational reporter cell line provides a unique opportunity for profiling large pharmacological and toxicological compound libraries for their effect on ERα levels as well as for assessing direct compound binding to the receptor, thus facilitating mechanistic studies by which compounds exert their biological effects on ERα.

Combined Effects of Zeta-potential and Temperature of Nanopores on Diffusioosmotic Ion Transport.

Diffusioosmosis (DO) results from ion transport near charged surfaces in the presence of electrolyte gradients and is critical in nanofluidic systems. However, DO has not yet been comprehensively studied because nanofabrication materials have limitations of low throughput and difficult quantification. Herein, we describe a self-assembled particle membrane (SAPM)-integrated microfluidic platform that can modulate the material properties (e.g., zeta-potential) and transport flux of nanopores. We quantify the effect of the zeta-potential on DO by measuring the electrical signals across three different nanopores/nanochannels of the SAPM. We then empirically quantify the effects of the temperature and ionic strength of the electrolytes on DO and reveal a nonlinear relationship with DO-driven ion transport; the ionic strengths govern the DO- or diffusion-effective ion transport phenomena. Finally, we demonstrate DO-driven electric power generation with enhanced performance as a potential application under optimized experimental conditions.

Advanced Point-of-Care Testing Technologies for Human Acute Respiratory Virus Detection.

The ever-growing global threats to human life caused by the human acute respiratory virus (RV) infections have cost billions of lives, created a significant economic burden, and shaped society for centuries. The timely response to emerging RVs could save human lives and reduce the medical care burden. The development of RV detection technologies is essential for potentially preventing RV pandemic and epidemics. However, commonly used detection technologies lack sensitivity, specificity, and speed, thus often failing to provide the rapid turnaround times. To address this problem, new technologies are devised to address the performance inadequacies of the traditional methods. These emerging technologies offer improvements in convenience, speed, flexibility, and portability of point-of-care test (POCT). Herein, recent developments in POCT are comprehensively reviewed for eight typical acute respiratory viruses. This review discusses the challenges and opportunities of various recognition and detection strategies and discusses these according to their detection principles, including nucleic acid amplification, optical POCT, electrochemistry, lateral flow assays, microfluidics, enzyme-linked immunosorbent assays, and microarrays. The importance of limits of detection, throughput, portability, and specificity when testing clinical samples in resource-limited settings is emphasized. Finally, the evaluation of commercial POCT kits for both essential RV diagnosis and clinical-oriented practices is included.

Multifunctional computing-in-memory SRAM cells based on two-surface-channel MoS2 transistors

SummaryDriven by technologies such as machine learning, artificial intelligence, and internet of things, the energy efficiency and throughput limitations of the von Neumann architecture are becoming more and more serious. As a new type of computer architecture, computing-in-memory is an alternative approach to alleviate the von Neumann bottleneck. Here, we have demonstrated two kinds of computing-in-memory designs based on two-surface-channel MoS2 transistors: symmetrical 4T2R Static Random-Access Memory (SRAM) cell and skewed 3T3R SRAM cell, where the symmetrical SRAM cell can realize in-memory XNOR/XOR computations and the skewed SRAM cell can achieve in-memory NAND/NOR computations. Furthermore, since both the memory and computing units are based on two-surface-channel transistors with high area efficiency, the two proposed computing-in-memory SRAM cells consume fewer transistors, suggesting a potential application in highly area-efficient and multifunctional computing chips.

Quantum Artificial Synapses

AbstractNeuromorphic in‐memory computing systems, comprising artificial synapses and neurons, can overcome the energy inefficiency and throughput limitation of today's von Neumann computing architecture. Recently, powered by the unique properties of quantum materials, for example, high mobility, outstanding sensitivity, and strong quantum effect, researchers have built quantum artificial synapses to mimic the biological ones. These quantum electronic/photonic synapses can precisely define their conductance state (or synaptic weight) for emulating synaptic behaviors, which shows bionic performance unreachable by other conventional materials. In this review, the significant achievements in quantum artificial synapses are summarized. First, potential quantum materials used in artificial synapses are discussed with particular attention to quantum dots, nanowires, layered materials, and quasi‐2DEG interfaces. Then, the major quantum effects that are utilized in quantum artificial synapses, for example, Josephson effect, quantum tunneling, and spin memory, are reviewed. In addition to the discussion on a single synaptic device, the macroscale integration into artificial visual systems and artificial nerve networks are also highlighted. Finally, the associated future research trends and target applications are also discussed.

Intact Mass Quantitation of Therapeutic Antibodies for Pharmacokinetic Studies Using Immuno-Purification.

The quantitation of therapeutic antibodies by mass spectrometry often utilizes a surrogate peptide approach following enzymatic digestion of the antibody. Although this approach has been widely adopted, it is labor intensive with limited throughput in most instances. In addition, this approach can pose challenges when attempting to infer details such as quantity and modification state of the intact analyte. Recent enhancements in instrumentation and sample preparation have enabled quantitation through mass spectrometry detection of the intact protein circumnavigating many limitations of the surrogate peptide approach. Presented here is a method for quantitative analysis of therapeutic monoclonal antibodies (mAb) at the fully intact level in a complex pharmacokinetic study. This methodology yielded sensitivity down to 0.1μg/mL from 30μL of a biological sample volume to be utilized across multiple preclinical species without the need for pooling.

Artificial Intelligence-Powered Automated Holotomographic Microscopy Enables Label-Free Quantitative Biology

Abstract:Holotomographic microscopy (HTM) measures the refractive index (RI) tomograms of living cells and tissues in three dimensions. The ability to observe biological processes at high spatial and temporal resolution opens uncharted territories for cell biologists, however, current HTM devices have a limited throughput. We show here the first automated multi-well plate-compatible HTM device, the CX-A. Thanks to state-of-the-art environment control and a new type of autofocus, the CX-A can record multiple conditions in parallel over large fields of view, while its software EVE supports automated single-cell segmentation and quantification. This opens the door to new applications for HTM, from drug screening to systems biology.

A Novel Adaptive OFO-OFDM Modulation for Visible Light Communication

Radio frequency techniques have been deployed in the past time for wireless communication and following its spectral crunch and limited throughput, the visible light spectrum with enormously large bandwidth and potentials for high throughput is being investigated in this work. This study is aimed at investigating and modeling a signal conditioning scheme in the visible light spectrum in view of enhancing the throughput of the network. To effectively enhance communication throughput, a possible solution is to deploy multicarrier techniques. In this work, an adaptive Optimized Flipped Optical (OFO) OFDM is proposed for improved throughput using Lagrange Multiplier and Broyden Fletcher Goldfarb Shanno Algorithm (BFGSA). The Lagrange Multiplier technique was used to formulate the model for the optimization of the throughput constrained by the bit error rate (BER) and the total subcarrier transmit power whereas the BFGSA was used for the estimation of the approximation to the Hessian matrix for the computation of the optimal throughput value. Results showed improved spectral efficiency in favor of the proposed algorithm when compared with the conventional schemes. Further validations revealed the performance superiority of the proposed algorithm when compared with Castel, Wyglinski and Bedeer algorithms under comparable operating conditions for a given average signal to noise ratio (SNR).

Broadband Fourier-transform silicon nitride spectrometer with wide-area multiaperture input

Integrated microspectrometers implemented in silicon photonic chips have gathered a great interest for diverse applications such as biological analysis, environmental monitoring, and remote sensing. These applications often demand high spectral resolution, broad operational bandwidth, and large optical throughput. Spatial heterodyne Fourier-transform (SHFT) spectrometers have been proposed to overcome the limited optical throughput of dispersive and speckle-based on-chip spectrometers. However, state-of-the-art SHFT spectrometers in near-infrared achieve large optical throughput only within a narrow operational bandwidth. Here we demonstrate for the first time, to the best of our knowledge, a broadband silicon nitride SHFT spectrometer with the largest light collecting multiaperture input (320×410µm2) ever implemented in an SHFT on-chip spectrometer. The device was fabricated using 248 nm deep-ultraviolet lithography, exhibiting over 13 dB of optical throughput improvement compared to a single-aperture device. The measured resolution varies between 29 and 49 pm within the 1260-1600 nm wavelength range.

Information Distribution in Multi-Robot Systems: Generic, Utility-Aware Optimization Middleware.

This work addresses the problem of what information is worth sending in a multi-robot system under generic constraints, e.g., limited throughput or energy. Our decision method is based on Monte Carlo Tree Search. It is designed as a transparent middleware that can be integrated into existing systems to optimize communication among robots. Furthermore, we introduce techniques to reduce the decision space of this problem to further improve the performance. We evaluate our approach using a simulation study and demonstrate its feasibility in a real-world environment by realizing a proof of concept in ROS 2 on mobile robots.

Embedded Metamaterial Subframe Patch for Increased Power Output of Piezoelectric Energy Harvesters

AbstractThese days, piezoelectric energy harvesting (PEH) is introduced as one of the clean and renewable energy sources for powering the self-powered sensors utilized for wireless condition monitoring of structures. However, low efficiency is the biggest drawback of PEHs. This paper introduces an innovative embedded metamaterial subframe (MetaSub) patch as a practical solution to address the low throughput limitation of conventional PEHs whose host structure has already been constructed or installed. To evaluate the performance of the embedded MetaSub patch (EMSP), a cantilever beam is considered as the host structure in this study. The EMSP transfers the auxetic behavior to the piezoelectric element (PZT) wherever substituting a regular beam with an auxetic beam is either impracticable or suboptimal. The concept of the EMSP is numerically validated, and the comsol multiphysics software was employed to investigate its performance when a cantilever beam is subjected to different amplitude and frequency. The finite element model results demonstrate that the harvesting power in cases that use the EMSP can be amplified up to 5.5 times compared to a piezoelectric cantilever energy harvester without patch. This paper opens up a great potential of using EMSP for different types of energy harvesting systems in biomedical, acoustics, civil, electrical, aerospace, and mechanical engineering applications.

Abstract 3014: A preclinical platform of PDX-derived cell lines as a tool for pharmacological screening and functional studies

Abstract Despite considerable progress in understanding the biology and genetics of cancer progression, the development of effective therapies against cancer need physiological and predictive preclinical models. In this context, patient-derived xenograft (PDX) models has become a standard tool as they reproduce accurately the behavior of tumor of origin, in term of histological and molecular phenotype and response to chemotherapy. Although PDXs in vivo models are indispensable for preclinical studies, they suffer from some limitations due to study costs related to tumor maintenance on mice, variable engraftment rate, growth delay and limited throughput for large-scale drug screening. To address this problem and propose a time a cost effective preclinical screening tool, we developed a panel of PDX-derived low-passage 2D cell lines as a convenient in vitro pre-screening platform to profile compound activity. Different PDX models including breast, lung, colon, melanoma, glioblastoma and hepatoblastoma were tested for their capacity to generate cell lines maintaining the characteristics of the parental PDX tumor and usable for in vitro assays. Today, we succeeded with a series of 50 PDX models with 83% success rate. Tumor cells isolated from PDX tumor tissue were cultured under different media and matrix conditions, allowing at least 5 passages in culture. A Short Tandem Repeat (STR) comparison profile was done with the parental PDX before performing a master bank. We performed short term 2D cytotoxicity assays and long term colony assays to compare cell lines in vitro drug sensitivity with their parental PDX in vivo drug response and overall, the results show that this panel reproduced the drug response profile of the original PDXs with chemotherapies, PARP inhibitors, an ADC (T-DM1) and FGFR-targeting therapies. Moreover, cellular models engrafted back onto mice showed in vivo response to chemotherapies similar to that of the parental PDX confirming the identical behavior of cell line/PDX couples. As the use of cellular models is still considered as a standard for early preclinical test to evaluate drug response before moving to in vivo assays, our PDX-derived cell line platform appeared to be a robust and relevant tool. Furthermore, since the main concern when using in vitro models is the representativeness of the results obtained when transposed to in vivo models, the similarities between cell lines and parental PDX should maximize success of further in vivo preclinical drug development. Citation Format: Olivier Deas, Sophie Banis, Kathleen Flosseau, Lea Sinayen, Enora Le Ven, Jean-Gabriel Judde, Stefano Cairo. A preclinical platform of PDX-derived cell lines as a tool for pharmacological screening and functional studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3014.

An integrated magneto-electrochemical device for the rapid profiling of tumour extracellular vesicles from blood plasma.

The analysis of proteins expressed on circulating extracellular vesicles (EVs) could facilitate the diagnosis of different types of cancers. EV assays however have lengthy sample workups and limited throughput and sensitivity, making them unsuitable for routine clinical use. Here, we report a high-throughput assay that integrates EV enrichment, via antibody-coated magnetic beads, with the detection of EV-bound antibodies, via an electrochemical reaction. The assay requires less than one hour, is performed on plasma samples, and its 96-well plate format enables measurements in parallel via a prototype reader. Using samples from patients with colorectal cancer or healthy volunteers, we identified a panel of biomarkers (EGFR, EpCAM, CD24, GPA33) in circulating EVs that, when combined, showed higher diagnostic accuracy (>96%) than conventional assays. In a prospective cohort, the combined biomarker profile enabled assigning patients to a high- or a low-risk 5-year disease-free survival group, and the serial monitoring of EVs during therapy showed values declined after surgery yet increased upon relapse. Biomarker panels from plasma EVs may be suitable for the non-invasive monitoring of disease trajectory.

Strategy for high-throughput identification of protein complexes by array-based multi-dimensional liquid chromatography-mass spectrometry

Comprehensive elucidation of the composition of multiprotein complexes in model organisms is essential to understand conserved biological systems, but large-scale mapping physical association networks is still challenging due to limited throughput of present methods. In this work, a strategy coupling array-based online two-dimensional liquid chromatography (array-based 2D-LC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was demonstrated for high throughput and in-depth identification of protein complexes from cultured human HeLa cell extracts. Mixed-bed ion-exchange column was employed as the first dimensional (1stD) separating mode and an array consisting of eight reversed phase columns was developed as the second dimensional (2ndD) mode. Taking advantage of array parallel strategy, this online system showed an 8-fold increase in throughput. After array-based online 2D-LC separation, altogether 256 × 2ndD fractions were collected for further LC-MS/MS analysis. Public databases of protein-protein interaction (PPI) and co-elution curves identified by LC-MS were applied to reconstruct the protein complexes. A rigorous inspection was operated by cataloging the protein complexes into chromatographic fractions to minimize the number of false positives. As result, a total number of 4,436 proteins were identified and 26,092 elution curves were graphed. A network consisting of 47,745 PPIs was established among 2,201 proteins and presented 1,530 putative protein complexes with high confidence. Most of the identified PPIs were linked to diverse biological processes and may reveal further disease mechanism and therapeutic strategy.

High-throughput quantitation of SARS-CoV-2 antibodies in a single-dilution homogeneous assay

SARS-CoV-2 emerged in late 2019 and has since spread around the world, causing a pandemic of the respiratory disease COVID-19. Detecting antibodies against the virus is an essential tool for tracking infections and developing vaccines. Such tests, primarily utilizing the enzyme-linked immunosorbent assay (ELISA) principle, can be either qualitative (reporting positive/negative results) or quantitative (reporting a value representing the quantity of specific antibodies). Quantitation is vital for determining stability or decline of antibody titers in convalescence, efficacy of different vaccination regimens, and detection of asymptomatic infections. Quantitation typically requires two-step ELISA testing, in which samples are first screened in a qualitative assay and positive samples are subsequently analyzed as a dilution series. To overcome the throughput limitations of this approach, we developed a simpler and faster system that is highly automatable and achieves quantitation in a single-dilution screening format with sensitivity and specificity comparable to those of ELISA.

Quantitative Analysis of Immunosuppressive Drugs Using Tungsten Disulfide Nanosheet-Assisted Laser Desorption Ionization Mass Spectrometry.

For organ transplantation patients, the therapeutic drug monitoring (TDM) of immunosuppressive drugs is essential to prevent the toxicity or rejection of the organ. Currently, TDM is done by immunoassays or liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods; however, these methods lack specificity or are expensive, require high levels of skill, and offer limited sample throughput. Although matrix-assisted (MA) laser desorption ionization (LDI) mass spectrometry (MS) can provide enhanced throughput and cost-effectiveness, its application in TDM is limited due to the limitations of the matrixes such as a lack of sensitivity and reproducibility. Here, we present an alternative quantification method for the TDM of the immunosuppressive drugs in the blood of organ transplant patients by utilizing laser desorption ionization mass spectrometry (LDI-MS) based on a tungsten disulfide nanosheet, which is well-known for its excellent physicochemical properties such as a strong UV absorbance and high electron mobility. By adopting a microliquid inkjet printing system, a high-throughput analysis of the blood samples with enhanced sensitivity and reproducibility was achieved. Furthermore, up to 80 cases of patient samples were analyzed and the results were compared with those of LC-MS/MS by using Passing-Bablok regression and Bland-Altman analysis to demonstrate that our LDI-MS platform is suitable to replace current TDM techniques. Our approach will facilitate the rapid and accurate analysis of blood samples from a large number of patients for immunosuppressive drug prescriptions.

Recent advances in rapid antimicrobial susceptibility testing systems

Introduction Until recently antimicrobial susceptibility testing (AST) methods based on demonstration of phenotypic susceptibility in 16-24 h remained largely unchanged. Areas covered Advances in rapid phenotypic and molecular-based AST systems. Expert opinion AST has changed over the past decade, with many rapid phenotypic and molecular methods developed to demonstrate phenotypic or genotypic resistance, or biochemical markers of resistance such as β-lactamases associated with carbapenem resistance. Most methods still require isolation of bacteria from specimens before both legacy and newer methods can be used. Bacterial identification by MALDI-TOF mass spectroscopy is now widely used and is often key to interpretation of rapid AST results. Several PCR arrays are available to detect the most frequent pathogens associated with bloodstream infections and their major antimicrobial resistance genes. Many advances in whole-genome sequencing of bacteria and fungi isolated by culture as well as directly from clinical specimens have been made but are not yet widely available. High cost and limited throughput are the major obstacles to uptake of rapid methods, but targeted use has allowed many laboratories to be able to use many of these systems. Continued development and decreasing costs are expected to result in more extensive use of these increasingly useful methods.