Biology subjects

Seth, A.

Publications and source records attributed to Seth, A..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Identification of a novel basal body-localized epsilon-tubulin in Leishmania

Epsilon-tubulins are unconventional isoforms of the tubulin family, found in only a few organisms so far. We identified a novel epsilon-tubulin in Leishmania major (Lme-tubulin) that exhibits significant sequence similarity and conservation of functional domains with its known counterparts. Lme-tubulin was found to be constitutively expressed in both the extracellular promastigote form of the parasite and the amastigotes residing within infected macrophages. For localization studies, we generated a Leishmania strain expressing mNeonGreen-tagged Lme-tubulin using CRISPR-Cas9-mediated endogenous protein tagging method. Imaging studies with this strain revealed Lme-tubulin to be localized near the kinetoplast and at the flagellar base, indicating a basal body localization. That Lme-tubulin is indeed localized at the basal body and not a part of the microtubular network was confirmed when its localization was found to remain unaltered upon treatment with nocodazole, a microtubule disruptor. This is the first experimental finding of an e-tubulin not only in the genus Leishmania but in the entire Trypanosomatidae family and is likely to incite further research to uncover the physiological role of this intriguing tubulin in this group of protozoan parasites. Summary StatementWe report for the first time an epsilon-tubulin in Leishmania parasite. This nocodazole-insensitive unconventional tubulin is expressed constitutively and found to be localized in the basal body.

cell biology↗

bioRxiv2024

Ligase-mediated programmable genomic integration (L-PGI): an efficient site-specific gene editing system that overcomes the limitations of reverse transcriptase-based editing systems

Since their discovery, CRISPR/Cas9 systems have been repurposed for programmable targeted genomic editing. This has led to unprecedented advancement of gene editing for therapeutic benefit. Initial uses of CRISPR/Cas9 were focused on gene disruption via DNA cleavage, but significant engineering led to systems for single base editing as well as insertion, deletion and manipulation of short stretches of genomic sequences using nicking Cas9 and RT-based methods. These technologies allowed safer and more precise editing but were limited to small corrections and showed significantly reduced efficiencies in nondividing cells, presenting difficulty for translation to in vivo therapies. To find an alternate editing strategy that could address these shortcomings, we revisited the mechanism of DNA nicking by nCas9. nCas9 nicking creates a free 5 phosphate group and a 3 hydroxyl group on the complementary strand of the target sequence. Under ordinary conditions in the cell these ends are re-joined by endogenously expressed ligases to repair DNA back to wild-type. If, however, a DNA fragment containing the desired edit were present, ligation of the nicked genomic DNA with the delivered fragment could result in gene editing. We demonstrate that optimization of each component and introduction of a chemically modified high affinity splinting DNA allows a variety of ligase-based edits, including longer edits not efficient with RT-based systems, at high efficiencies and fidelities that minimize genomic byproducts in both dividing and nondividing cells as well as in vivo in adult mice. Here we present the first therapeutically relevant ligation-based programmable gene editing technology, L-PGI.

bioengineering↗

bioRxiv2024

Non-canonical Wnt signaling triggered by WNT2B drives adrenal aldosterone production

The steroid hormone aldosterone, produced by the zona glomerulosa (zG) of the adrenal gland, is a master regulator of plasma electrolytes and blood pressure. While aldosterone control by the renin-angiotensin system is well understood, other key regulatory factors have remained elusive. Here, we replicated a prior association between a non-coding variant in WNT2B and an increased risk of primary aldosteronism, a prevalent and debilitating disease caused by excessive aldosterone production. We further show that in both mice and humans, WNT2B is expressed in the mesenchymal capsule surrounding the adrenal cortex, in close proximity to the zG. Global loss of Wnt2b in the mouse results in a dysmorphic and hypocellular zG, with impaired aldosterone production. Similarly, humans harboring WNT2B loss-of-function mutations develop a novel form of Familial Hyperreninemic Hypoaldosteronism, designated here as Type 4. Additionally, we demonstrate that WNT2B signals by activating the non-canonical Wnt/planar cell polarity pathway. Our findings identify WNT2B as a key regulator of zG function and aldosterone production with important clinical implications. HighlightsO_LIWNT2B variant is associated with increased risk for primary aldosteronism C_LIO_LIWnt2b knock-out mice show defects in adrenal morphology C_LIO_LIWnt2b knock-out mice have hyperreninemic hypoaldosteronism C_LIO_LIWNT2B activates non-canonical Wnt/planar cell polarity signaling C_LIO_LIWNT2B deficiency causes a new form of familial hyperreninemic hypoaldosteronism C_LI

genetics↗

bioRxiv2024

Global analysis of protein turnover dynamics in single cells

Even with recent improvements in sample preparation and instrumentation, single-cell proteomics (SCP) analyses mostly measure protein abundances, making the field unidimensional. In this study, we employ a pulsed stable isotope labeling by amino acids in cell culture (SILAC) approach to simultaneously evaluate protein abundance and turnover in single cells (SC-pSILAC). Using state-of-the-art SCP workflow, we demonstrated that two SILAC labels are detectable from [~]4000 proteins in single HeLa cells recapitulating known biology. We investigated drug effects on global and specific protein turnover in single cells and performed a large-scale time-series SC-pSILAC analysis of undirected differentiation of human induced pluripotent stem cells (iPSC) encompassing six sampling times over two months and analyzed >1000 cells. Abundance measurements highlighted cell-specific markers of stem cells and various organ-specific cell types. Protein turnover dynamics highlighted differentiation-specific co-regulation of core members of protein complexes with core histone turnover discriminating dividing and non-dividing cells with potential in stem cell and cancer research. Our study represents the most comprehensive SCP analysis to date, offering new insights into cellular diversity and pioneering functional measurements beyond protein abundance. This method distinguishes SCP from other single-cell omics approaches and enhances its scientific relevance in biological research in a multidimensional manner.

systems biology↗

bioRxiv2024

Automated single-cell proteomics providing sufficient proteome depth to study complex biology beyond cell type classifications

Mass spectrometry (MS)-based single-cell proteomics (SCP) has gained massive attention as a viable complement to other single cell approaches. The rapid technological and computational advances in the field have pushed the boundaries of sensitivity and throughput. However, reproducible quantification of thousands of proteins within a single cell at reasonable proteome depth to characterize biological phenomena remains a challenge. To address some of those limitations we present a combination of fully automated single cell sample preparation utilizing a dedicated chip within the picolitre dispensing robot, the cellenONE. The proteoCHIP EVO 96 can be directly interfaced with the Evosep One chromatographic system for in-line desalting and highly reproducible separation with a throughput of 80 samples per day. This, in combination with the Bruker timsTOF MS instruments, demonstrates double the identifications without manual sample handling. Moreover, relative to standard high-performance liquid chromatography, the Evosep One separation provides further 2-fold improvement in protein identifications. The implementation of the newest generation timsTOF Ultra with our proteoCHIP EVO 96-based sample preparation workflow reproducibly identifies up to 4,000 proteins per single HEK-293T without a carrier or match-between runs. Our current SCP depth spans over 4 orders of magnitude and identifies over 50 biologically relevant ubiquitin ligases. We complement our highly reproducible single-cell proteomics workflow to profile hundreds of lipopolysaccharide (LPS)-perturbed THP-1 cells and identified key regulatory proteins involved in interleukin and interferon signaling. This study demonstrates that the proteoCHIP EVO 96-based SCP sample preparation with the timsTOF Ultra provides sufficient proteome depth to study complex biology beyond cell-type classifications.

biochemistry↗

bioRxiv2024

NEUROG2 regulates a human-specific neurodevelopmental gene regulatory program

Unique hallmarks of human neocortical development include slower rates of neurogenesis and the establishment of an extracellular matrix-rich, outer-subventricular zone that supports basal neural progenitor cell expansion. How gene regulatory networks have evolved to support these human-specific neurodevelopmental features is poorly understood. Mining single cell data from cerebral organoids and human fetal cortices, we found that NEUROG2 expression is enriched in basal neural progenitor cells. To identify and purify NEUROG2-expressing cells and trace their short-term lineage, we engineered two NEUROG2-mCherry knock-in human embryonic stem cell lines to produce cerebral organoids. Transcriptomic profiling of mCherry-high organoid cells revealed elevated expression of PPP1R17, associated with a fast-evolving human-accelerated regulatory region, oligodendrocyte precursor cell and extracellular matrix-associated gene transcripts. Conversely, only neurogenic gene transcripts were enriched in mCherry-high cortical cells from Neurog2:mCherry knock-in mice. Finally, we show that Neurog2 is sufficient to induce Ppp1r17, which slows human neural progenitor cell division, and Col13a1, an extracellular matrix gene, in P19 cells. NEUROG2 thus regulates a human neurodevelopmental gene regulatory program implicated in supporting a pro-proliferative basal progenitor cell niche and tempering the neurogenic pace. SUMMARY STATEMENTTranscriptomic analyses of NEUROG2-mCherry knock-in human embryonic stem cell-derived cerebral organoids reveal a link between NEUROG2 and extracellular matrix remodeling during human cortical development.

developmental biology↗

bioRxiv2023

Empowering human-like walking with a bio-inspired gait controller for an under-actuated torque- driven human model

Human gait simulation plays a crucial role in providing insights into various aspects of locomotion, such as diagnosing injuries and impairments, assessing abnormal gait patterns, and developing assistive and rehabilitation technologies. To achieve more realistic results in gait simulation, it is necessary to utilize a comprehensive model that closely replicates the kinematics and kinetics of the human gait pattern. OpenSim software provides anthropomorphic and anatomically accurate human skeletal structures that enable users to create personalized models for individuals to accurately replicate real human behavior. However, torque-driven models face challenges in balancing unactuated degrees of freedom during forward dynamic simulations. Adopting a bio-inspired strategy that ensures an individuals balance with a minimized energy expenditure, this paper proposes a gait controller for a torque-deriven OpenSim model to achieve a stable walking. The proposed controller takes a model-based approach to calculate a "Balance Equivalent Control Torque" and uses the concept of the hip-ankle strategy to distribute this balance torque to the lower-limb joints. To optimize the controller gains and the "Balance Distribution Coefficients", an interface is stablished between MATLAB and OpenSim that is capable of conducting controllable forward dynamic simulations. The simulation results demonstrate that the torque-driven model can walk naturally with joint torques suitably matching experimental data. The robustness of the bio-inspired gait controller is also assessed by applying a range of external forces on the upper body to disturb the model. The robustness analysis demonstrates the quick and effective balance recovery mechanism of the proposed bio-inspired controller.

bioengineering↗

bioRxiv2023

An automated and fast sample preparation workflow for laser microdissection guided ultrasensitive proteomics

Spatial tissue proteomics integrating whole-slide imaging, laser microdissection and ultrasensitive mass spectrometry is a powerful approach to link cellular phenotypes to functional proteome states in (patho)physiology. To be applicable to large patient cohorts and low sample input amounts, including single-cell applications, loss-minimized and streamlined end-to-end workflows are key. We here introduce an automated sample preparation protocol for laser microdissected samples utilizing the cellenONE(R) robotic system, which has the capacity to process 192 samples in three hours. Following laser microdissection collection directly into the proteoCHIP LF 48 or EVO 96 chip, our optimized protocol facilitates lysis, formalin de-crosslinking and tryptic digest of low-input archival tissue samples. The seamless integration with the Evosep ONE LC system by centrifugation allows on-the-fly sample clean-up, particularly pertinent for laser microdissection workflows. We validate our method in human tonsil archival tissue, where we profile proteomes of spatially-defined B-cell, T-cell and epithelial microregions of 4,000 {micro}m2 to a depth of [~]2,000 proteins and with high cell type specificity. We finally provide detailed equipment templates and experimental guidelines for broad accessibility.

systems biology↗

bioRxiv2023

High-throughput and scalable single cell proteomics identifies over 5000 proteins per cell

The emergence of mass spectrometry (MS)-based single-cell proteomics (SCP) promise to revolutionize the study of cellular biology and biomedicine by providing an unparalleled view of the proteome in individual cells. Despite its groundbreaking potential, SCP is nascent and faces challenges including limited sequence depth, throughput, and reproducibility, which have constrained its broader utility. This study introduces key methodological advances, which considerably improve the sensitivity, coverage and dependability of protein identification from single cells. We developed an almost lossless SCP workflow encompassing sample preparation to MS analysis, doubling the number of identified proteins from roughly 2000 to over 5000 in individual HeLa cells. A comprehensive evaluation of analytical software tools, alongside strict false discovery rate (FDR) controls solidified the reliability of our results. These enhancements also facilitated the direct detection of post-translational modifications (PTMs) in single cells, negating the need for enrichment and thereby simplifying the analytical process. Although throughput in MS remains a challenge, our study demonstrates the feasibility of processing up to 80 label-free SCP samples per day. Moreover, an optimized tissue dissociation buffer enabled effective single cell disaggregation of drug-treated cancer cell spheroids, refining the overall proteomic analysis. Our workflow sets a new benchmark in SCP for sensitivity and throughput, with broad applications ranging from the study of cellular development to disease progression and the identification of cell type-specific markers and therapeutic targets.

systems biology↗

bioRxiv2023

Does enforcing glenohumeral joint stability matter? A new rapid muscle redundancy solver highlights the importance of non-superficial shoulder muscles

The complexity of the human shoulder girdle enables the large mobility of the upper extremity, but also introduces instability of the glenohumeral (GH) joint. Shoulder movements are generated by coordinating large superficial and deeper stabilizing muscles spanning numerous degrees-of-freedom. How shoulder muscles are coordinated to stabilize the movement of the GH joint remains widely unknown. Musculoskeletal simulations are powerful tools to gain insights into the actions of individual muscles and particularly of those that are difficult to measure. In this study, we analyze how enforcement of GH joint stability in a musculoskeletal model affects the estimates of individual muscle activity during shoulder movements. To estimate both muscle activity and GH stability from recorded shoulder movements, we developed a Rapid Muscle Redundancy (RMR) solver to include constraints on joint reaction forces (JRFs) from a musculoskeletal model. The RMR solver yields muscle activations and joint forces by minimizing the weighted sum of squared-activations, while matching experimental motion. We implemented three new features: first, computed muscle forces include active and passive fiber contributions; second, muscle activation rates are enforced to be physiological, and third, JRFs are efficiently formulated as linear functions of activations. Muscle activity from the RMR solver without GH stability was not different from the computed muscle control (CMC) algorithm and electromyography of superficial muscles. The efficiency of the solver enabled us to test 3600 trials sampled within the uncertainty of the experimental movements to test the differences in muscle activity with and without GH joint stability enforced. We found that enforcing GH stability significantly increases the estimated activity of the rotator cuff muscles but not of most superficial muscles. Therefore, a comparison of shoulder model muscle activity to EMG measurements of superficial muscles alone is insufficient to validate the activity of rotator cuff muscles estimated from musculoskeletal models.

systems biology↗

bioRxiv2023

Genome editing in the mouse brain with minimally immunogenic Cas9 RNPs

Transient delivery of CRISPR-Cas9 ribonucleoproteins (RNPs) into the central nervous system (CNS) for therapeutic genome editing could avoid limitations of viral vector-based delivery including cargo capacity, immunogenicity, and cost. Here we tested the ability of cell penetrant Cas9 RNPs to edit the mouse striatum when introduced using a convection enhanced delivery system. These transient Cas9 RNPs showed comparable editing of neurons and reduced adaptive immune responses relative to one formulation of Cas9 delivered using AAV serotype 9. The production of ultra-low-endotoxin Cas9 protein manufactured at scale further improved innate immunity. We conclude that injection-based delivery of minimally immunogenic CRISPR genome editing RNPs into the CNS provides a valuable alternative to virus-mediated genome editing.

bioengineering↗

bioRxiv2022

Minimization of metabolic cost of transport predicts changes in gait mechanics over a range of ankle-foot orthosis stiffnesses in individuals with bilateral plantar flexor weakness

Neuromuscular disorders often lead to ankle plantar flexor muscle weakness, which impairs ankle push-off power and forward propulsion during gait. To improve walking speed and reduce metabolic cost of transport (mCoT), patients with plantar flexor weakness are provided dorsal-leaf spring ankle-foot orthoses (AFOs). The mCoT during gait depends on the AFO stiffness where an optimal AFO stiffness exists that minimizes mCoT. The biomechanics of why and how there exists a unique optimal stiffness for individuals with plantar flexor weakness are not well understood. To help understand why, we hypothesized that gait adaptations can be predicted by mCoT minimization. To explain how, we hypothesized that the AFO would reduce the required support moment and, hence, metabolic costs from the ankle plantar flexor and knee extensor muscles during stance and reduce hip flexor metabolic cost to initiate swing. To test these hypotheses, we generated neuromusculoskeletal simulations to represent gait of an individual with bilateral plantar flexor weakness wearing an AFO with varying stiffness. Predictions were predicated on the goal of minimizing mCoT at each stiffness level, and the motor patterns were determined via dynamic optimization. The simulation results were compared to experimental data from subjects with bilateral plantar flexor weakness walking with varying AFO-stiffness. Our simulations demonstrated that minimization of mCoT predicts gait adaptations in response to varying AFO stiffness levels in individuals with bilateral plantar flexor weakness. Initial reductions in mCoT with increasing stiffness were attributed to reductions in quadriceps metabolic cost during midstance. Increases in mCoT above optimum stiffness were attributed to the increasing metabolic cost of both hip flexor and hamstrings muscles. The insights gained from our simulations could inform clinicians on the prescription of personalized AFOs. With further model individualization, simulations based on mCoT minimization may sufficiently predict adaptations to an AFO in individuals with plantar flexor weakness. Author SummaryNeuromuscular disorders like stroke, Charcot-Marie-Tooth disease, and poliomyelitis often lead to calf muscle weakness, which makes walking slower and more demanding. To improve walking speed and reduce energy demand, patients with calf muscle weakness are frequently provided ankle-foot orthoses (AFOs). The energy demand of walking is affected by the AFOs stiffness and there is a stiffness that minimizes the energy demand for an individual with calf weakness. To uncover the optimal stiffness, we generated simulations of an individual with calf muscle weakness walking with an AFO over a range of stiffnesses. Stable walking patterns were generated that minimized the energy demand for a given stiffness. We found that the initial reductions in energy demand as stiffness increased, were attributed to reductions in quadriceps muscle energy. Increases in energy demand as stiffness increased above the optimum were attributed to the increased energetic cost of both hip flexor and hamstrings muscles. With further model individualization, we believe that simulations based on minimizing the energy demand of movement can sufficiently predict adaptations to an AFO. Simulations can enable the prescription of personalized AFOs for individuals with neuromuscular disorders that help them walk with sufficient speed and efficiency to keep up with their peers.

bioengineering↗

bioRxiv2022

Single cell preparations of Mycobacterium tuberculosis damage the mycobacterial envelope and disrupt macrophage interactions

For decades, investigators have studied the interaction of Mycobacterium tuberculosis (Mtb) with macrophages, which serve as a major cellular niche for the bacilli. Because Mtb are prone to aggregation, investigators rely on varied methods to disaggregate the bacteria for these studies. Here, we examined the impact of routinely used preparation methods on bacterial cell envelop integrity, macrophage inflammatory responses, and intracellular Mtb survival. We found that both gentle sonication and filtering damaged the mycobacterial cell envelope and markedly impacted the outcome of macrophage infections. Unexpectedly, sonicated bacilli were hyperinflammatory, eliciting dramatically higher TLR2-dependent gene expression and elevated secretion of IL-1{beta} and TNF-. Despite evoking enhanced inflammatory responses, sonicated bacilli replicated normally in macrophages. In contrast, Mtb that had been passed through a filter induced little inflammatory response, and they were attenuated in macrophages. Previous work suggests that the mycobacterial cell envelope lipid, phthiocerol dimycocerosate (PDIM), dampens macrophage inflammatory responses to Mtb. However, we found that the impact of PDIM depended on the method used to prepare Mtb. In conclusion, widely used methodologies to disaggregate Mtb may introduce experimental artifacts in Mtb-host interaction studies, including alteration of host inflammatory signaling, intracellular bacterial survival, and interpretation of bacterial mutants.

microbiology↗

bioRxiv2022

Structure-based Discovery of Conformationally Selective Inhibitors of the Serotonin Transporter

The serotonin transporter (SERT) removes synaptic serotonin and is the target of anti-depressant drugs. SERT adopts three conformations: outward-open, occluded, and inward-open. All known inhibitors target the outward-open state except ibogaine, which has an unusual anti-depressant profile and stabilizes the inward-open conformation. Unfortunately, ibogaine is promiscuous and cardiotoxic, limiting understanding of inward-open state ligands. We computationally docked over 200 million small molecules against the ibogaine stabilized inward-open state of SERT. Thirty-six top-ranking compounds were synthesized and thirteen inhibited with potencies ranging from 29 to 5000 nM. Structure-based optimization led to two novel inhibitors with Ki values down to 3 nM. The new molecules stabilized an outward-closed state of the transporter and had little activity against off-targets. A cryo-EM structure of one of these bound to SERT confirmed the predicted geometry. In mouse behavioral assays, both had anxiolytic and anti-depressant activity, with potencies up to 200 better than fluoxetine.

biochemistry↗

bioRxiv2022

Parallel measurement of transcriptomes and proteomes from same single cells using nanodroplet splitting

Single-cell multiomics provides comprehensive insights into gene regulatory networks, cellular diversity, and temporal dynamics. Here, we introduce nanoSPLITS (nanodroplet SPlitting for Linked-multimodal Investigations of Trace Samples), an integrated platform that enables global profiling of the transcriptome and proteome from same single cells using RNA sequencing and mass spectrometry-based proteomics, respectively. Benchmarking of nanoSPLITS demonstrated excellent measurement precision, with deep proteomic and transcriptomic profiling of single-cells. We applied nanoSPLITS to cyclin-dependent kinase 1 inhibited cells and found phospho-signaling events could be quantified alongside global protein and mRNA measurements, providing new insights into cell cycle regulation. We also extended nanoSPLITS to single-cells isolated from human pancreatic islets, introducing an efficient approach for facile identification of unknown cell types, and detecting their protein markers by mapping transcriptomic data to existing large-scale single-cell RNA sequencing reference databases. Herein, we establish nanoSPLITS as a new multiomic technology incorporating global proteomics and anticipate the approach will be critical to furthering our understanding of single-cell systems.

systems biology↗

bioRxiv2022

Distinct glycerophospholipids potentiate Gsα-activated adenylyl cyclase activity

Nine mammalian adenylyl cyclases (AC) are pseudoheterodimers with two hexahelical membrane domains which are isoform-specifically conserved. Previously we proposed that these membrane domains are orphan receptors (10.7554/eLife.13098; 10.1016/j.cellsig.2020.109538). Lipids extracted from fetal bovine serum at pH 1 inhibited several mAC activities. Guided by a lipidomic analysis we tested glycerophospholipids as potential ligands. Contrary to expectations we surprisingly discovered that 1-stearoyl-2-docosahexaenoyl-phosphatidic acid (SDPA) potentiated Gs-activated activity of human AC isoform 3 seven-fold. The specificity of fatty acyl esters at glycerol positions 1 and 2 was rather stringent. 1-Stearoyl-2-docosahexaenoyl-phosphatidylserine and 1-stearoyl-2-docosahexaenoyl-phosphatidylethanolamine significantly potentiated several Gs-activated mAC isoforms to different extents. SDPA appears not interact with forskolin activation of AC isoform 3. SDPA enhanced Gs-activated AC activities in membranes from mouse brain cortex. The action of SDPA was reversible. Unexpectedly, SDPA did not affect cAMP generation in HEK293 cells stimulated by isoproterenol, PGE2 and adenosine, virtually excluding a role as an extracellular ligand and, instead, suggesting an intracellular role. In summary, we discovered a new dimension of intracellular AC regulation by chemically defined glycerophospholipids.

biochemistry↗

bioRxiv2022

Psychedelics and schizophrenia: Distinct alterations to Bayesian inference

Schizophrenia and states induced by certain psychotomimetic drugs may share some physiological and phenomenological properties, but they differ in fundamental ways: one is a crippling chronic mental disease, while the others are temporary, pharmacologically-induced states presently being explored as treatments for mental illnesses. Building towards a deeper understanding of these different alterations of normal consciousness, here we compare the changes in neural dynamics induced by LSD and ketamine (in healthy volunteers) against those associated with schizophrenia, as observed in resting-state M/EEG recordings. While both conditions exhibit increased neural signal diversity, our findings reveal that this is accompanied by an increased transfer entropy from the front to the back of the brain in schizophrenia, versus an overall reduction under the two drugs. Furthermore, we show that these effects can be reproduced via different alterations of standard Bayesian inference applied on a computational model based on the predictive processing framework. In particular, the effects observed under the drugs are modelled as a reduction of the precision of the priors, while the effects of schizophrenia correspond to an increased precision of sensory information. These findings shed new light on the similarities and differences between schizophrenia and two psychotomimetic drug states, and have potential implications for the study of consciousness and future mental health treatments.

neuroscience↗

bioRxiv2021

OpenSense: An open-source toolbox for Inertial-Measurement-Unit-based measurement of lower extremity kinematics over long durations

BackgroundThe ability to measure joint kinematics in natural environments over long durations using inertial measurement units (IMUs) could enable at-home monitoring and personalized treatment of neurological and musculoskeletal disorders. However, drift, or the accumulation of error over time, inhibits the accurate measurement of movement over long durations. We sought to develop an open-source workflow to estimate lower extremity joint kinematics from IMU data that was accurate, and capable of assessing and mitigating drift. MethodsWe computed IMU-based estimates of kinematics using sensor fusion and an inverse kinematics approach with a constrained biomechanical model. We measured kinematics for 11 subjects as they performed two 10-minute trials: walking and a repeated sequence of varied lower-extremity movements. To validate the approach, we compared the joint angles computed with IMU orientations to the joint angles computed from optical motion capture using root mean square (RMS) difference and Pearson correlations, and estimated drift using a linear regression on each subjects RMS differences over time. ResultsIMU-based kinematic estimates agreed with optical motion capture; median RMS differences over all subjects and all minutes were between 3-6 degrees for all joint angles except hip rotation and correlation coefficients were moderate to strong (r = 0.60 to 0.87). We observed minimal drift in the RMS differences over ten minutes; the average slopes of the linear fits to these data were near zero (-0.14 to 0.17 deg/min). ConclusionsOur workflow produced joint kinematics consistent with those estimated by optical motion capture, and could mitigate kinematic drift even in the trials of continuous walking without rest, obviating the need for explicit sensor recalibration (e.g. sitting or standing still for a few seconds or zero-velocity updates) used in current drift-mitigation approaches. This could enable long-duration measurements, bringing the field one step closer to estimating kinematics in natural environments.

bioengineering↗