Sensitive Readout Research Articles

Automated long-range compensation of an rf quantum dot sensor

Charge sensing is a sensitive technique for probing quantum devices, of particular importance for spin-qubit readout. To achieve good readout sensitivities, the proximity of the charge sensor to the device to be measured is a necessity. However, this proximity also means that the operation of the device affects, in turn, the sensor tuning and ultimately the readout sensitivity. We present an approach for compensating for this crosstalk effect allowing for the gate voltages of the measured device to be swept in a 1-V × 1-V window while maintaining a sensor configuration chosen by a Bayesian optimizer. Our algorithm will hopefully be a major contribution to the suite of fully automated solutions required for the operation of large quantum device architectures. Published by the American Physical Society 2024

Nanomechanical detection to empower robust monitoring of sepsis and microbial adaptive immune system-mediated proinflammatory disease

The correlation between circulating microbes and sepsis as well as proinflammatory diseases is increasingly gaining recognition. However, the detection of microbes’ cell-free DNA (cfDNA), which exist at concentrations of a billion times lower than blood proteins, poses a significant challenge for early disease detection. Here, we present Nano mechanics combined with highly sensitive readout sequences to address the challenges of ultralow counts of disease biomarkers, thus enabling robust quantitative monitoring of chronic medical conditions at different stages of human disease progression. To showcase the effectiveness of our approach, we employ fragments of cfDNA and human cell secretory proteins as models with predictive capabilities for human diseases. Notably, our method reveals a reliable representation over an impressive three to four orders of magnitude in the detection limit and dynamic range, surpassing commercially available quantitative polymerase chain reaction (qPCR) commonly used in routine clinical practice. This concept underpins a highly sensitive and selective medical device designed for the early detection of circulating microbes in patients undergoing intensive cancer therapy. This will help pinpoint individuals at risk of complications, including damage to the intestinal barrier and development of neutropenic fever/Sirsa/Sepsis. Moreover, this approach introduces new avenues for stratifying antibiotic prophylaxis in proinflammatory diseases.

Single-cell analysis of osmoregulation reveals heterogeneity of aquaporin 4 functionality in human astrocytes.

The water channel aquaporin 4 (AQP4) contributes to water flow and waste removal across the blood-brain barrier and its levels, organization and localization are perturbed in various neurological diseases, including Alzheimer's Disease. This renders AQP4 a potentially valuable therapeutic target. However, most functional assays aimed at identifying modulators of AQP4 function are performed with primary rodent cells and do not consider inter-cellular variations in AQP4 abundance and presentation. To address this, we have established and applied a robust live cell microscopy assay that captures the contribution of AQP4 in the osmotically driven (de-)quenching of the vital dye Calcein-AM with single-cell resolution. Using human astrocytoma cells, we found that performing measurements on cellular regions instead of whole fields of view yielded a more sensitive readout of the osmotic response, which correlated with AQP4 abundance. Stable co-expression of the two major AQP4 isoforms, but not of the individual isoforms, provoked a faster adaptation to osmotic changes, while siRNA-mediated knockdown of AQP4 had the opposite effect. Post-hoc correlation with the canonical membrane marker CD44 revealed that the speed of the osmotic response scaled with AQP4 membrane enrichment. Coating the substrate with laminin promoted AQP4 membrane enrichment, while cell confinement with fixed-size micropatterns further increased the speed of osmoregulation, underscoring the influence of extracellular factors. The osmotic response of primary fetal astrocytes and human iPSC-derived astrocyte models was comparable to AQP4-deficient astrocytoma cells, in line with their low AQP4 levels and indicative of their immature state. In conclusion, a correlative single-cell approach based on the quantification of Calcein-AM quenching capacity, AQP4 abundance and AQP4 membrane enrichment, allows resolving osmoregulation in a more sensitive manner and reveals heterogeneity between and within human astrocyte (-like) cultures, which could prove crucial for future screens aimed at identifying AQP4 modulators.

Magnetic microbead-based upconversion immunoassay with laser-induced breakdown spectroscopy readout for the detection of prostate-specific antigen.

Laser-induced breakdown spectroscopy (LIBS) is a promising technique for the readout of immunochemical assays utilizing indirect detection of labels (Tag-LIBS), typically based on nanoparticles. We have previously demonstrated that Tag-LIBS immunoassay employing yttrium-based photon-upconversion nanoparticles (UCNPs) can reach sensitivity similar to commonly used enzyme and fluorescence immunoassays. In this study, we report on further increasing the sensitivity of UCNP-based Tag-LIBS immunoassay by employing magnetic microbeads (MBs) as the solid phase in the determinationof cancer biomarker prostate-specific antigen. Due to the possibility of analyte preconcentration, MBs enabled achieving a limit of detection (LOD) of 4.0pg·mL-1, representing two orders of magnitude improvement compared withequivalent microtiter plate-based assay (LOD of 460pg·mL-1). In addition, utilizing MBs opens up the possibility of an internal standardization of the LIBS readout by employing iron spectral lines, which improves the assay robustness by compensating for LIBS signal fluctuations and bead-bound immunocomplexes lost throughout the washing steps. Finally, the practical applicability of the technique was confirmed by the successful analysis of clinical samples, showing a strong correlation with the standard electrochemiluminescence immunoassay. Overall, MB-based Tag-LIBS was confirmed as a promising immunoassay approach, combining fast readout, multiplexing possibilities, and high sensitivity approaching upconversion luminescence scanning while avoiding the requirement of luminescence properties of labels.

Retinoblastoma protein activity revealed by CRISPRi study of divergent Rbf1 and Rbf2 paralogs.

Retinoblastoma tumor suppressor proteins (Rb) are highly conserved metazoan transcriptional corepressors involved in regulating the expression of thousands of genes. The vertebrate lineage and the Drosophila genus independently experienced an Rb gene duplication event, leading to the expression of several Rb paralogs whose unique and redundant roles in gene regulation remain to be fully explored. Here, we used a novel CRISPRi system in Drosophila to identify the significance of paralogy in the Rb family. We engineered dCas9 fusions to the fly Rbf1 and Rbf2 paralogs and deployed them to gene promoters in vivo, studying them in their native chromatin context. By directly querying the in vivo response of dozens of genes to Rbf1 and Rbf2 targeting, using both transcriptional as well as sensitive developmental readouts, we find that Rb paralogs function as "soft repressors" and have highly context-specific activities. Our comparison of targeting endogenous genes to reporter genes in cell culture identified striking differences in activity, underlining the importance of using CRISPRi effectors in a physiologically relevant context to identify paralog-specific activities. Our study uncovers the complexity of Rb-mediated transcriptional regulation in a living organism, and serves as a stepping stone for future CRISPRi development in Drosophila.

Minor changes to circulating steroid hormones in female rats after perinatal exposure to diethylstilbestrol or ketoconazole

Current chemical test strategies lack sensitive markers for detecting female reproductive toxicity caused by endocrine disrupting chemicals (EDCs). In search of a potentially sensitive readout, the steroidogenic disrupting effects of the well-known EDCs ketoconazole (KTZ) and diethylstilbestrol (DES) were investigated in vitro and on circulating steroid hormones in perinatally exposed female Sprague-Dawley rats. Twenty-one steroid hormones were analysed using LC-MS/MS in plasma from female rat offspring at postnatal day (PD) 6, 14, 22, 42 and 90. Most circulating steroid hormone levels increased with age except for estrone (E1), estradiol (E2) and backdoor pathway androsterone (ANDROST), which decreased after PD 22. Perinatal exposure to DES did not affect circulating steroid hormone levels at any dose or age compared to controls. KTZ exposure resulted in dose-dependent increase of corticosterone (CORTICO) at PD 6 and PD 14, with statistical significance only at PD 14. In the in vitro gold standard H295R steroidogenesis assay, twenty-one steroid hormones were measured instead of only T and E2. DES had subtle effects on steroidogenesis, whereas KTZ decreased most steroid hormones, but increased CORTICO, progesterone (P4), estriol (E3) initially (around 0.1–1 µM) before decreasing. Our data suggests that circulating steroidomic profiling may not be a sensitive readout for EDC-induced female reproductive toxicity. Further studies are needed to associate H295R assay steroidomic profiles with in vivo profiles, especially in target tissues such as adrenals or gonads. Expanding the H295R steroidogenic assay to include a comprehensive steroidomic profile may enhance its regulatory applicability.

Assessing signs of central sensitization: A critical review of physiological measures in experimentally induced secondary hyperalgesia.

Central sensitization (CS) is believed to play a role in many chronic pain conditions. Direct non-invasive recording from single nociceptive neurons is not feasible in humans, complicating CS establishment. This review discusses how secondary hyperalgesia (SHA), considered a manifestation of CS, affects physiological measures in healthy individuals and if these measures could indicate CS. It addresses controversies about heat sensitivity changes, the role of tactile afferents in mechanical hypersensitivity and detecting SHA through electrical stimuli. Additionally, it reviews the potential of neurophysiological measures to indicate CS presence. Four databases, PubMed, ScienceDirect, Scopus and Cochrane Library, were searched using terms linked to 'hyperalgesia'. The search was limited to research articles in English conducted in humans until 2023. Evidence for heat hyperalgesia in the SHA area is sparse and seems to depend on the experimental method used. Minimal or no involvement of tactile afferents in SHA was found. At the spinal level, the threshold of the nociceptive withdrawal reflex (RIII) is consistently reduced during experimentally induced SHA. The RIII area and the spinal somatosensory potential (N13-SEP) amplitude are modulated only with long-lasting nociceptive input. At the brain level, pinprick-evoked potentials within the SHA area are increased. Mechanical pinprick hyperalgesia is the most reliable behavioural readout for SHA, while the RIII threshold is the most sensitive neurophysiological readout. Due to scarce data on reliability, sensitivity and specificity, none of the revised neurophysiological methods is currently suitable for CS identification at the individual level. Gathering evidence for CS in humans is a crucial research focus, especially with the increasing interest in concepts such as 'central sensitization-like pain' or 'nociplastic pain'. This review clarifies which readouts, among the different behavioural and neurophysiological proxies tested in experimental settings, can be used to infer the presence of CS in humans.

AI-assisted 3D analysis of grasping and reaching behavior of squirrel monkeys during recovery from cervical spinal cord injury

We have previously demonstrated that machine learning-based video analysis, conducted via DeepLabCut, is more sensitive for detecting subtle deficits in hand grasping behavior than traditional end-point performance assessments. This superiority was observed in a nonhuman primate (NHP) model of cervical spinal cord injury, specifically a dorsal column lesion (DCL). The current study aims to further characterize the kinematic aspects of the deficits in hand reaching, grasping, and retrieving behavior from a 3D perspective following a DCL. Squirrel monkeys were trained to retrieve sugar pellets from eight wells, which were located either on a flat plate or a raised tube with varying well depths. This setup was designed to require coordinated finger movements during the task. Immediately after the DCL, the animals exhibited measurable behavioral deficits. These were characterized by significant increases in grasping speed squared and trial completion time, markedly widened movement trajectories of individual fingers, and abnormalities in inter-finger distance and orientation. Increased task difficulty was associated with more pronounced behavioral deficits. By three months post-DCL, video-based measurements indicated no significant recovery, even though global end-point performance had returned to baseline levels. Our findings demonstrate that deprivation of tactile information results in impaired dexterous hand behavior involving coordinated finger movements, and the impairment is sustained for 20 weeks. This spinal cord injury (SCI) model, along with DeepLapCut analysis, provides a valuable platform for separately evaluating sensory and motor functions and their contributions to dexterous hand behavior and may be used for evaluating therapeutic interventions using more sensitive behavioral outcome readouts.

Comparative analysis of tardigrade locomotion across life stage, species, and disulfiram treatment.

Animal locomotion requires coordination between the central and peripheral nervous systems, between sensory inputs and motor outputs, and between nerves and muscles. Analysis of locomotion thus provides a comprehensive and sensitive readout of nervous system function and dysfunction. Tardigrades, the smallest known walking animals, coordinate movement of their eight legs with a relatively simple nervous system, and are a promising model for neuronal control of limb-driven locomotion. Here, we developed open-source tools for automated tracking of tardigrade locomotion in an unconstrained two-dimensional environment, for measuring multiple parameters of individual leg movements, and for quantifying interleg coordination. We used these tools to analyze >13,000 complete strides in >100 tardigrades, and identified preferred walking speeds and distinct step coordination patterns associated with those speeds. In addition, the rear legs of tardigrades, although they have distinct anatomy and step kinematics, were nonetheless incorporated into overall patterns of interleg coordination. Finally, comparisons of tardigrade locomotion across lifespan, between species, and upon disulfiram treatment suggested that neuronal regulation of high-level aspects of walking (e.g. speed, turns, walking bout initiation) operate independently from circuits controlling individual leg movements and interleg coordination.

A protein expression atlas on tissue samples and cell lines from cancer patients provides insights into tumor heterogeneity and dependencies.

The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) are foundational resources in cancer research, providing extensive molecular and phenotypic data. However, large-scale proteomic data across various cancer types for these cohorts remain limited. Here, we expand upon our previous work to generate high-quality protein expression data for approximately 8,000 TCGA patient samples and around 900 CCLE cell line samples, covering 447 clinically relevant proteins, using reverse-phase protein arrays. These protein expression profiles offer profound insights into intertumor heterogeneity and cancer dependency and serve as sensitive functional readouts for somatic alterations. We develop a systematic protein-centered strategy for identifying synthetic lethality pairs and experimentally validate an interaction between protein kinase A subunit α and epidermal growth factor receptor. We also identify metastasis-related protein markers with clinical relevance. This dataset represents a valuable resource for advancing our understanding of cancer mechanisms, discovering protein biomarkers and developing innovative therapeutic strategies.

Dissociable effects of mild COVID-19 on short- and long-term memories.

Recent studies have highlighted the presence of cognitive deficits following COVID-19 that persist beyond acute infection, regardless of the initial disease severity. Impairments in short- and long-term memory are among the core deficits reported by patients and observed in objective tests of memory performance. We aimed to extend previous studies by examining performance in a task that allows us to directly compare and contrast memories at different timescales. More specifically, we assessed both short- and long-term memories for contextual-spatial associations encoded during a common session and probed at different durations using an equivalent task in non-hospitalized individuals recovering from mild COVID-19 compared to healthy controls. The approach equated all aspects of memory materials and response demands, isolating performance changes resulting only from memory timescales and thus allowing us to quantify the impact of COVID-19 on cognition. In addition to providing measures of accuracy and response times, the task also provided a sensitive continuous readout of the precision of memory representations, specifically by examining the resolution with which spatial locations were retained in memory. The results demonstrated selective impairment of long-term memory performance in individuals recovering from mild COVID-19 infection. Short-term memory performance remained comparable to healthy controls. Specifically, poor precision of long-term memory representations was demonstrated, which improved with days since diagnosis. No such relationship was observed for short-term memory performance. Our findings reveal a specific impairment to the precision of spatial-contextual long-term memory representations in individuals recovering from mild COVID-19 and demonstrate evidence of recovery in long-term memory over time. Further, the experimental design provides a carefully controlled and sensitive framework to assess memory across different durations with the potential to provide more detailed phenotyping of memory deficits associated with COVID-19 in general.

Quantum Enhanced Balanced Heterodyne Readout for Differential Interferometry.

Conventional heterodyne readout schemes are now under reconsideration due to the realization of techniques to evade its inherent 3dB signal-to-noise penalty. The application of high-frequency, quadrature-entangled, two-mode squeezed states can further improve the readout sensitivity of audio-band signals. In this Letter, we experimentally demonstrate quantum-enhanced heterodyne readout of two spatially distinct interferometers with direct optical signal combination, circumventing the 3dB heterodyne signal-to-noise penalty. Applying a high-frequency, quadrature-entangled, two-mode squeezed state, we show further signal-to-noise improvement of an injected audio band signal of 3.5dB. This technique is applicable for quantum-limited high-precision experiments, with application to searches for quantum gravity, searches for dark matter, gravitational wave detection, and wavelength-multiplexed quantum communication.

Quantum paraelectric varactors for radiofrequency measurements at millikelvin temperatures

Radiofrequency reflectometry can provide fast and sensitive electrical read-out of charge and spin qubits in quantum dot devices coupled to resonant circuits. In situ frequency tuning and impedance matching of the resonator circuit using voltage-tunable capacitors (varactors) is needed to optimize read-out sensitivity, but the performance of conventional semiconductor- and ferroelectric-based varactors degrades substantially in the millikelvin temperature range relevant for solid-state quantum devices. Here we show that strontium titanate and potassium tantalate, materials which can exhibit quantum paraelectric behaviour with large field-tunable permittivity at low temperatures, can be used to make varactors with perfect impedance matching and resonator frequency tuning at 6 mK. We characterize the varactors at 6 mK in terms of their capacitance tunability, dissipative losses and magnetic field insensitivity. We use the quantum paraelectric varactors to optimize the radiofrequency read-out of carbon nanotube quantum dot devices, achieving a charge sensitivity of 4.8 μe Hz−1/2 and a capacitance sensitivity of 0.04 aF Hz−1/2.

Coherent Addressing of Single Molecular Electron Spin Qubits

AbstractWith rational designability, versatile tunability, and quantum coherence, molecular electron spin qubits could offer new opportunities for quantum information science, enabling simplified implementation of quantum algorithms and chemical‐specific quantum sensing. The development of these transformative technologies relies on coherent addressing of single molecular electron spin qubits with high initialization, manipulation, and readout fidelities. This is unfeasible to conventional electron spin resonance spectroscopy, which is widely used for coherent addressing of ensemble electron spins, due to its low initialization efficiency and readout sensitivity. Taking advantage of single spin detectability of single‐molecule spectroscopy, scanning tunneling microscopy, atomic force microscopy, and quantum metrology, several strategies have been developed to empower electron spin resonance spectroscopy with single qubit addressability. In this Emerging Topic, we introduce principles and technical implementation of strategies for coherent addressing of single molecular electron spin qubits, discuss their potential applicability in quantum technologies, and point out their challenges in terms of scalability, molecular design, and/or decoherence suppression. We discuss future directions to overcome these challenges and to improve single qubit addressing technologies, which will facilitate the advancement of molecular quantum information science.

High-Throughput Determination of Infectious Virus Titers by Kinetic Measurement of Infection-Induced Changes in Cell Morphology.

Infectivity assays are the key analytical technology for the development and manufacturing of virus-based therapeutics. Here, we introduce a novel assay format that utilizes label-free bright-field images to determine the kinetics of infection-dependent changes in cell morphology. In particular, cell rounding is directly proportional to the amount of infectious virus applied, enabling rapid determination of viral titers in relation to a standard curve. Our kinetic infectious virus titer (KIT) assay is stability-indicating and, due to its sensitive readout method, provides results within 24 h post-infection. Compared to traditional infectivity assays, which depend on a single readout of an infection endpoint, cumulated analysis of kinetic data by a fit model results in precise results (CV < 20%) based on only three wells per sample. This approach allows for a high throughput with ~400 samples processed by a single operator per week. We demonstrate the applicability of the KIT assay for the genetically engineered oncolytic VSV-GP, Newcastle disease virus (NDV), and parapoxvirus ovis (ORFV), but it can potentially be extended to a wide range of viruses that induce morphological changes upon infection. The versatility of this assay, combined with its independence from specific instruments or software, makes it a promising solution to overcome the analytical bottleneck in infectivity assays within the pharmaceutical industry and as a routine method in academic research.

Membrane protein MHZ3 regulates the on-off switch of ethylene signaling in rice

Ethylene regulates plant growth, development, and stress adaptation. However, the early signaling events following ethylene perception, particularly in the regulation of ethylene receptor/CTRs (CONSTITUTIVE TRIPLE RESPONSE) complex, remains less understood. Here, utilizing the rapid phospho-shift of rice OsCTR2 in response to ethylene as a sensitive readout for signal activation, we revealed that MHZ3, previously identified as a stabilizer of ETHYLENE INSENSITIVE 2 (OsEIN2), is crucial for maintaining OsCTR2 phosphorylation. Genetically, both functional MHZ3 and ethylene receptors prove essential for OsCTR2 phosphorylation. MHZ3 physically interacts with both subfamily I and II ethylene receptors, e.g., OsERS2 and OsETR2 respectively, stabilizing their association with OsCTR2 and thereby maintaining OsCTR2 activity. Ethylene treatment disrupts the interactions within the protein complex MHZ3/receptors/OsCTR2, reducing OsCTR2 phosphorylation and initiating downstream signaling. Our study unveils the dual role of MHZ3 in fine-tuning ethylene signaling activation, providing insights into the initial stages of the ethylene signaling cascade.

Programmable Plasmonic Hydrogel Thermometers Actuated by DNA Breathing

AbstractNanothermometry explores the use of temperature‐dependent properties of materials for remote and sensitive thermal readout at the nanoscale. The currently established nanothermometers are largely limited by uncontrollable nanoparticle flocculation, complex experimental setup, and narrow working temperature range. Here it is shown that gold nanoparticles (e.g., spheres, rods) embedded in a hydrogel can afford sensitive, durable, and range‐tunable temperature sensing via the terminal breathing of the nanoparticle surface‐grafted DNA. The realization of the plasmonic hydrogel thermometer with a thermal sensitivity of ≤2 °C relies on the dynamically modulable interparticle spacing by thermo‐responsive terminal base pairing/unpairing of the surface DNA. By altering the alcoholic ratio of the hydrogel, the temperature‐response range can be continuously regulated based on solvent‐mediated DNA base pairing. Compared with the colloidal counterpart, importantly, the hydrogel thermometer exhibits greatly improved thermal sensing capability (e.g., repeatability ≥50 times) while possessing excellent durability. Given the excellent durability, high sensitivity, and programmable temperature response range, the thermometers actuated by DNA breathing for advanced uses in human sensing and optoelectronics are within reach.

Radiatively cooled quantum microwave amplifiers

Superconducting microwave amplifiers are essential for sensitive signal readout in superconducting quantum processors. Typically based on Josephson junctions, these amplifiers require operation at milli-Kelvin temperatures to achieve quantum-limited performance. Here, we demonstrate a quantum microwave amplifier that employs radiative cooling to operate at elevated temperatures and maintain near quantum-limited added noise. This kinetic-inductance-based parametric amplifier, patterned from a single layer of relatively high-Tc NbN thin film, maintains a high gain and meanwhile enables low added noise of 1.3 quanta when operated at 1.5 K. Remarkably, this represents only a 0.2 quanta increase compared to the performance at a base temperature of 0.1 K. Based on our findings, we also discuss the practicality of such an operating scheme for various quantum applications. By uplifting the parametric amplifiers from the mixing chamber without compromising readout efficiency, this work represents an important step toward more scalable microwave quantum technologies.

Membrane Proteins in Action Monitored by pH-Responsive Liquid Crystal Biosensors.

Liquid crystal (LC) biosensors have received significant attention for their potential applications for point-of-care devices due to their sensitivity, low cost, and easy read-out. They have been employed to detect a wide range of important biological molecules. However, detecting the function of membrane proteins has been extremely challenging due to the difficulty of integrating membrane proteins, lipid membranes, and LCs into one system. In this study, we addressed this challenge by monitoring the proton-pumping function of bacteriorhodopsin (bR) using a pH-sensitive LC thin film biosensor. To achieve this, we deposited purple membranes (PMs) containing a 2D crystal form of bRs onto an LC-aqueous interface. Under light, the PM patches changed the local pH at the LC-aqueous interface, causing a color change in the LC thin film that is observable through a polarizing microscope with crossed polarizers. These findings open up new opportunities to study the biofunctions of membrane proteins and their induced local environmental changes in a solution using LC biosensors.

Brain Feature Extraction With an Artifact-Tolerant Multiplexed Time-Encoding Neural Frontend for True Real-Time Closed-Loop Neuromodulation.

Closed-loop neuromodulation is emerging as a more effective and targeted solution for the treatment of neurological symptoms compared to traditional open-loop stimulation. The majority of the present designs lack the ability to continuously record brain activity during electrical stimulation; hence they cannot fully monitor the treatment's effectiveness. This is due to the large stimulation artifacts that can saturate the sensitive readout circuits. To overcome this challenge, this work presents a rapid-artifact-recovery time-multiplexed neural readout frontend in combination with backend linear interpolation to reconstruct the artifact-corrupted local field potentials' (LFP) features. Our hybrid technique is an alternative approach to avoid power-hungry large-dynamic-range readout architectures or large and complex artifact template subtraction circuits. We discuss the design and measurements of a prototype implementation of the proposed readout frontend in 180-nm CMOS. It combines time multiplexing and time-domain conversion in a novel 13-bit incremental ADC, requiring only 0.0018 mm2/channel of readout area despite the large 180-nm CMOS process used, while consuming only 4.51 μW/channel. This is the smallest reported area for stimulation-voltage-compatible technologies (i.e. ≥ 65 nm). The frontend also yields a best-in-class peak total harmonic distortion of -72.6 dB @2.5-mVpp input, thanks to its implicit DAC mismatch-error shaping property. We employ the chip to measure brain LFP signals corrupted with artifacts, then perform linear interpolation and feature extraction on the measured signals and evaluate the reconstruction quality, using a set of sixteen commonly used features and three stimulation scenarios. The results show relative accuracies above 95% with respect to the situation without artifacts. This work is an ideal candidate for integration in high-channel-count true closed-loop neuromodulation systems.