Biology subjects

Nguyen, A. T.

Publications and source records attributed to Nguyen, A. T..

33 records · Page 2Linked to original sources

bioRxiv2022

Motor Cortex Excitability in Chronic Low Back Pain

IntroductionChronic pain is associated with dysfunctional cortical excitability. Research has identified altered intracortical motor cortex excitability in Chronic Lower Back Pain (CLBP). However, research identifying the specific intracortical changes underlying CLBP has been met with inconsistent findings. In the present case-control study, we examined intracortical excitability of the primary motor cortex using transcranial magnetic stimulation (TMS) in individuals with CLBP. MethodsTwenty participants with CLBP (Mage = 54.45 years, SDage = 15.89 years) and 18 age- and gender-matched, pain-free controls (M = 53.83, SD = 16.72) were included in this study. TMS was applied to the hand motor area of the right hemisphere and motor evoked potentials (MEPs) were recorded from the first dorsal interosseous muscle of the contralateral hand. Resting motor threshold (rMT) and MEP amplitude were measured using single-pulse stimulation. Short intracortical inhibition (SICI) and intracortical facilitation (ICF) were assessed using paired-pulse stimulation. ResultsIndividuals with CLBP had significantly higher rMT (decreased corticospinal excitability) and reduced ICF compared to controls. No significant differences were found in MEP amplitude and SICI. ConclusionThese findings add to the growing body of evidence that CLBP is associated with deficits in intracortical modulation involving glutamatergic mechanisms. SignificanceThis article reports chronic lower back pain is associated with changes in intracortical excitability, specifically reduced intracortical facilitation. Furthermore, the imbalance between facilitation and inhibition may be related to pain intensity. These findings may help clinicians in the treatment of chronic pain with an increased focus on using neuromodulation techniques, targeting maladaptive intracortical facilitation, as a potential therapeutic tool in chronic pain.

neuroscience↗

bioRxiv2022

COVID-19 vaccine booster induces a strong CD8+ T cell response against Omicron variant epitopes in HLA-A*02:01+ individuals

The >30 mutated residues in the Omicron spike protein have led to its rapid classification as a new SARS-CoV-2 variant of concern. As a result, Omicron may escape from the immune system, decreasing the protection provided by COVID-19 vaccines. Preliminary data shows a weaker neutralizing antibody response to Omicron compared to the ancestral SARS-CoV-2 virus, which can be increased after a booster vaccine. Here, we report that CD8+ T cells can recognize Omicron variant epitopes presented by HLA-A*02:01 in both COVID-19 recovered and vaccinated individuals, even 6 months after infection or vaccination. Additionally, the T cell response was stronger for Omicron variant epitopes after the vaccine booster. Altogether, T cells can recognize Omicron variants, especially in vaccinated individuals after the vaccine booster. One-Sentence SummaryCD8+ T cells response against Omicron variant epitopes is stronger after the vaccine booster.

immunology↗

bioRxiv2021

Molecular basis of a dominant SARS-CoV-2 Spike-derived epitope presented by HLA-A*02:01 recognised by a public TCR

The data currently available on how the immune system recognizes the SARS-CoV-2 virus is growing rapidly. While there are structures of some SARS-CoV-2 proteins in complex with antibodies, which helps us understand how the immune system is able to recognise this new virus, we are lacking data on how T cells are able to recognize this virus. T cells, especially the cytotoxic CD8+ T cells, are critical for viral recognition and clearance. Here we report the X-ray crystallography structure of a T cell receptor, shared among unrelated individuals (public TCR) in complex with a dominant spike-derived CD8+ T cell epitope (YLQ peptide). We show that YLQ activates a polyfunctional CD8+ T cell response in COVID-19 recovered patients. We detail the molecular basis for the shared TCR gene usage observed in HLA-A*02:01+ individuals, providing an understanding of TCR recognition towards a SARS-CoV-2 epitope. Interestingly, the YLQ peptide conformation did not change upon TCR binding, facilitating the high-affinity interaction observed.

immunology↗

bioRxiv2021

Identification of Cancer-Associated Fibroblasts in Glioblastoma and Defining Their Pro-tumoral Effects

Despite their identification in some cancers, pro-tumoral cancer-associated fibroblasts (CAFs) were presumed absent in glioblastoma given the lack of brain fibroblasts. Serial trypsinization of primary glioblastoma cultures yielded cells with CAF morphology, CAF transcriptomic profile, and mesenchymal lineage in single-cell RNA-seq. Glioblastoma CAFs were attracted to glioblastoma stem cells (GSCs) and CAFs enriched GSCs. We created a resource of inferred crosstalk by mapping expression of receptors to their cognate ligands, identifying PDGF-{beta} and TGF-{beta} as mediators of GSC effects on CAFs, and osteopontin and hepatocyte growth factor as mediators of CAF-induced GSC enrichment. Glioblastoma CAFs also induced M2 macrophage polarization by producing the EDA fibronectin variant. Glioblastoma CAFs were enriched in the subventricular zone which houses neural stem cells that produce GSCs. Including CAFs in GSC-derived xenografts induced in vivo growth. These findings are among the first to identify glioblastoma CAFs and their GSC interactions, making them an intriguing target.

cancer biology↗

bioRxiv2021

Engagement of the contralateral limb can enhance the facilitation of motor output by loud acoustic stimuli

When intense sound is presented during light muscle contraction, inhibition of the corticospinal tract is observed. During action preparation, this effect is reversed, with sound resulting in excitation of the corticospinal tract. We investigated how the combined maintenance of a muscle contraction during preparation for a ballistic action impacts the magnitude of the facilitation of motor output by a loud acoustic stimulus (LAS) - a phenomenon known as the StartReact effect. Participants executed ballistic wrist flexion movements and a LAS was presented simultaneously with the imperative signal in a subset of trials. We examined whether the force level or muscle used to maintain a contraction during preparation for the ballistic response impacted reaction time and/or the force of movements triggered by the LAS. These contractions were sustained either ipsilaterally or contralaterally to the ballistic response. The magnitude of facilitation by the LAS was greatest when low force flexion contractions were maintained in the limb contralateral to the ballistic response during preparation. There was little change in facilitation when contractions recruited the contralateral extensor muscle, or when they were sustained in the same limb that executed the ballistic response. We conclude that a larger network of neurons which may be engaged by a contralateral sustained contraction prior to initiation may be recruited by the LAS, further contributing to the motor output of the response. These findings may be particularly applicable in stroke rehabilitation where engagement of the contralesional side may increase the benefits of a LAS to the functional recovery of movement.

neuroscience↗

bioRxiv2021

Integrated spatial multi-omics reveals fibroblast fate during tissue repair

In the skin, tissue injury results in fibrosis in the form of scars composed of dense extracellular matrix deposited by fibroblasts. The therapeutic goal of regenerative wound healing has remained elusive in part because principles of fibroblast programming and adaptive response to injury remain incompletely understood. Here, we present a multimodal -omics platform for the comprehensive study of cell populations in complex tissue, which has allowed us to characterize the cells involved in wound healing across both time and space. We employ a stented wound model that recapitulates human tissue repair kinetics and multiple Rainbow transgenic lines to precisely track fibroblast fate during the physiologic response to injury. Through integrated analysis of single cell chromatin landscapes and gene expression states, coupled with spatial transcriptomic profiling, we are able to impute fibroblast epigenomes with temporospatial resolution. This has allowed us to define the mechanisms controlling cell fate during migration, proliferation, and differentiation following tissue injury and thereby reexamine the canonical phases of wound healing. These findings have broad implications for the study of tissue repair in complex organ systems.

bioinformatics↗

bioRxiv2021

Deep Learning-Based Approaches for Decoding Motor Intent from Peripheral Nerve Signals

The ultimate goal of an upper-limb neuroprosthesis is to achieve dexterous and intuitive control of individual fingers. Previous literature shows that deep learning (DL) is an effective tool to decode the motor intent from neural signals obtained from different parts of the nervous system. However, it still requires complicated deep neural networks that are inefficient and not feasible to work in real-time. Here we investigate different approaches to enhance the efficiency of the DL-based motor decoding paradigm. First, a comprehensive collection of feature extraction techniques is applied to reduce the input data dimensionality. Next, we investigate two different strategies for deploying DL models: a one-step (1S) approach when big input data are available and a two-step (2S) when input data are limited. With the 1S approach, a single regression stage predicts the trajectories of all fingers. With the 2S approach, a classification stage identifies the fingers in motion, followed by a regression stage that predicts those active digits trajectories. The addition of feature extraction substantially lowers the motor decoders complexity, making it feasible for translation to a real-time paradigm. The 1S approach using a recurrent neural network (RNN) generally gives better prediction results than all the ML algorithms with mean squared error (MSE) ranges from 10-3 to 10-4 for all finger while variance accounted for (VAF) scores are above 0.8 for the most degree of freedom (DOF). This result reaffirms that DL is more advantageous than classic ML methods for handling a large dataset. However, when training on a smaller input data set as in the 2S approach, ML techniques offers a simpler implementation while ensuring comparably good decoding outcome to the DL ones. In the classification step, either machine-learning (ML) or DL models achieve the accuracy and F1 score of 0.99. Thanks to the classification step, in the regression step, both types of models result in comparable MSE and VAF scores as those of the 1S approach. Our study outlines the trade-offs to inform the implementation of real-time, low-latency, and high accuracy DL-based motor decoder for clinical applications.

bioengineering↗

bioRxiv2020

A Bioelectric Neural Interface Towards Intuitive Prosthetic Control For Amputees

ObjectiveWhile prosthetic hands with independently actuated digits have become commercially available, state-of-the-art human-machine interfaces (HMI) only permit control over a limited set of grasp patterns, which does not enable amputees to experience sufficient improvement in their daily activities to make an active prosthesis useful. ApproachHere we present a technology platform combining fully-integrated bioelectronics, implantable intrafascicular microelectrodes and deep learning-based artificial intelligence (AI) to facilitate this missing bridge by tapping into the intricate motor control signals of peripheral nerves. The bioelectric neural interface includes an ultra-low-noise neural recording system to sense electroneurography (ENG) signals from microelectrode arrays implanted in the residual nerves, and AI models employing the recurrent neural network (RNN) architecture to decode the subjects motor intention. Main resultsA pilot human study has been carried out on a transradial amputee. We demonstrate that the information channel established by the proposed neural interface is sufficient to provide high accuracy control of a prosthetic hand up to 15 degrees of freedom (DOF). The interface is intuitive as it directly maps complex prosthesis movements to the patients true intention. SignificanceOur study layouts the foundation towards not only a robust and dexterous control strategy for modern neuroprostheses at a near-natural level approaching that of the able hand, but also an intuitive conduit for connecting human minds and machines through the peripheral neural pathways. Clinical trialDExterous Hand Control Through Fascicular Targeting (DEFT). Identifier: NCT02994160.

bioengineering↗

bioRxiv2020

Responses to Loud Acoustic Stimuli: Short and Long Timescale Effects on Cortical and Sub-Cortical Preparation Reflect Conditional Probability.

The presentation of Loud Acoustic Stimuli (LAS) during preparation can trigger motor actions at very short latencies in a phenomenon called the StartReact effect. It was initially proposed that a special, separate sub-cortical mechanism which by-passes slower cortical processes could be involved. We sought to examine the evidence for a separate mechanism against the alternative that responses to LAS can be explained by a combination of stimulus intensity effects and preparatory-states - as proposed by activation models of motor control. To investigate whether cortically mediated preparatory processes are involved in shaping reactions to LAS, we used an auditory reaction task where we manipulated preparation-level within each trial. We contrasted responses to non-intense tones and LAS and examined whether cortical activation, sub-cortical excitability (measured by pre-stimulus EEG and eye-blink startle reflexes, respectively) and the motor response were influenced by preparation-level. As predicted by the activation model, increases in preparation-level were marked by gradual reductions in RT coupled with increases in cortical activation and sub-cortical excitability - at both condition- and trial-levels. Changes in cortical activation influenced motor and auditory but not visual areas - highlighting the wide-spread yet selective nature of preparation. RTs were shorter to LAS than tones, but the overall pattern of preparation-level effects were the same for both stimuli. These results demonstrate that LAS responses are indeed shaped by cortically mediated preparatory processes. The concurrent changes observed in brain and behaviour with increasing preparation reinforces the notion that preparation is marked by evolving brain states which shape the motor response. Key PointsO_LIReactions to Loud Acoustic Stimuli can be explained by stimulus intensity and preparation state C_LIO_LIWe manipulated movement preparation by altering the temporal position of the imperative stimulus C_LIO_LIPreparation was marked by reductions in RT, and increased cortical and sub-cortical excitability C_LIO_LIPreparation had the same effect on reactions to Loud Acoustic Stimuli and non-intense tones C_LIO_LIThe results highlight the widespread, evolving, and strategic nature of movement preparation C_LI

neuroscience↗

bioRxiv2020

Preparatory Suppression and Facilitation of Voluntary and Involuntary Responses to Loud Acoustic Stimuli in an Anticipatory Timing Task.

In this study, we sought to characterise the effects of intense sensory stimulation at different stages of preparation for an anticipated action on voluntary and involuntary behaviours. In our experiment, we presented unexpected loud acoustic stimuli (LAS) at four critical times during movement preparation to probe the state of the nervous system (Baseline, -1192 ms, -392 ms, and 0 ms relative to expected movement onset), and measured their effect on voluntary and involuntary motor actions (finger-press and eye-blink startle reflex, respectively). Voluntary responses were largely facilitated by the LAS, leading to earlier and more forceful responses compared to Control and Baseline conditions. Notably, voluntary responses were significantly facilitated on trials where the LAS was presented early during preparation (-1192 ms). Eye-blink reflexes elicited by the LAS at -392 ms were significantly reduced and delayed compared to other time-points, indicating suppression of sub-cortical excitability. Despite being in a suppressive state, voluntary responses on these trials were still facilitated by the LAS. The results provide insight into the mechanisms involved in preparing anticipatory actions. Induced activation can persist in the nervous system and can modulate subsequent actions for a longer time period than previously thought, highlighting that movement preparation is a continuously evolving process that is susceptible to external influence throughout the preparation period. Suppression of sub-cortical excitability shortly before movement onset is consistent with previous work showing corticospinal suppression which may be a necessary step before the execution of any voluntary response.

neuroscience↗

bioRxiv2020

Copper nanoparticle application enhances plant growth and grain yield in maize under drought stress conditions

Abiotic stresses, including drought, detrimentally affect the growth and productivity of many economically important crop plants, leading to significant yield losses, which can result in food shortages and threaten the sustainability of agriculture. Balancing between plant growth and stress responses is one of the most important characters for agricultural application to maximize plant production. In this study, we initially report that copper nanoparticle priming positively regulates drought stress responses in maize. The copper nanoparticle priming plants displayed enhanced drought tolerance indicated by their higher leaf water content and plant biomass under drought as compared with water-treated plants. Moreover, our data showed that the treatment of copper nanoparticle on plants increased anthocyanin, chlorophyll and carotenoid contents compared to water-treated plants under drought stress conditions. Additionally, histochemical analyses with nitro blue tetrazolium and 3,3-diaminobenzidine revealed that reactive oxygen species accumulation of priming plants was decreased as a result of enhancement of reactive oxygen species scavenging enzyme activities under drought. Furthermore, our comparative yield analysis data indicated applying copper nanoparticle to plant increased total seed number and grain yield under drought stress conditions. Our data provided the evidences that copper nanoparticle regulates plant protective mechanisms associated with drought tolerance, which is a promising approach for the production of drought tolerant crop plants.

plant biology↗

bioRxiv2019

Improved Automatic Pharmacovigilance: An Enhancement to the MedWatcher Social System for Monitoring Adverse Events

Traditional pharmacovigilance systems rely on adverse event reports received by regulatory authorities such as the United States Food and Drug Administration (FDA). These traditional systems suffer from underreporting and are not timely due to their reliance on third-party sentinels. To address these issues, the MedWatcher Social system for monitoring adverse events through automated processing of digital social media data and crowdsourcing was launched in 2012 by Boston Childrens Hospital and the FDA. The system is rooted in the well-established FDA MedWatch system.\n\nMedWatcher Social uses an indicator score approach to identify adverse events. This study evaluates the MedWatcher Social adverse event classifiers performance on Twitter data and proposes an enhancement to the indicator score method that results in improved adverse event identification.\n\nOur research suggests that automatic pharmacovigilance systems using the original indicator score approach should be updated. Careful consideration of modeling assumptions is critical when designing algorithms for computational epidemiology, and algorithms should be regularly reevaluated to identify enhancements and to remedy concept drift.

bioinformatics↗

bioRxiv2019

Motor Output Matters: A Study on the Neural Correlates of Failed Inhibitory-Control.

Motor actions can be suppressed with varying degrees of success, but this variability is not captured in many experiments where responses are represented in binary (response vs. no-response). Although the Stop/No-go P300 (an enhanced frontocentral positivity in the event-related potential (ERP) peaking around 300 ms after a Stop/No-go stimulus, compared to Go trials) has been implicated as a measure of inhibitory-control, it is unclear how the range of motor outputs relates to the P300. We examined the nature of this association in two experiments using an Anticipatory Timing and a Go/No-go Task. Force, response onset time, and the P300 were measured.\n\nIn both experiments, our results showed that trial-by-trial P300 amplitude on Failed Inhibitions were continuously related to Force, where higher response forces (reflecting a greater degree of error) were associated with smaller P300 amplitudes. Compared to Successful Inhibitions, P300 amplitude was reduced and ERP onset latencies were delayed on Failed Inhibitions. Although the binary categorisation of inhibition-success (Successful vs. Failed) accounted for more variance in the data compared to force, it misses a reliable linear relationship that can be captured by continuous measures of motor output. Overall, the results provide strong evidence that the engagement of inhibitory-control varies on a continuum from trial-to-trial and that this engagement is reflected by the P300. We present an activation-to-threshold model of inhibitory-control to explain our results, which offers a new conceptual framework for describing the implementation of inhibitory-control in highly prepared motor responses. Our results also highlight the importance of studying the spectrum of motor outputs and the need for future models of inhibitory-control to account for motor output.

neuroscience↗

bioRxiv2018

Proteomic analysis of the Pseudomonas aeruginosa iron starvation response reveals PrrF sRNA-dependent regulation of amino acid metabolism, iron-sulfur cluster biogenesis, motility, and zinc homeostasis

Iron is a critical nutrient for most microbial pathogens, and the innate immune system exploits this requirement by sequestering iron and other metals through a process termed nutritional immunity. The opportunistic pathogen Pseudomonas aeruginosa provides a model system for understanding the microbial response to host iron depletion, as this organism exhibits a high requirement for iron as well as an exquisite ability to overcome iron deprivation during infection. Hallmarks of P. aeruginosas iron starvation response include the induction of multiple high affinity iron acquisition systems and an \"iron sparing response\" that is post-transcriptionally mediated by the PrrF small regulatory RNAs (sRNAs). Here, we used liquid chromatography-tandem mass spectrometry to conduct label-free proteomics of the P. aeruginosa iron starvation response, revealing several iron-regulated processes that have not been previously described. Iron starvation induced multiple proteins involved in branched chain and aromatic amino acid catabolism, providing the capacity for iron-independent entry of carbons into the TCA cycle. Proteins involved in sulfur assimilation and cysteine biosynthesis were reduced upon iron starvation, while proteins involved in iron-sulfur cluster biogenesis were paradoxically increased, highlighting the central role of iron in P. aeruginosa metabolism. Iron starvation also resulted in changes in the expression of several zinc-responsive proteins, as well as the first experimental evidence for increased levels of twitching motility proteins upon iron starvation. Subsequent proteomics analyses demonstrated that the PrrF sRNAs were required for iron regulation of many of these newly-identified proteins, and we identified PrrF complementarity with mRNAs encoding key iron-regulated proteins involved in amino acid metabolism, iron-sulfur biogenesis, and zinc homeostasis. Combined, these results provide the most comprehensive view of the P. aeruginosa iron starvation response to date and outline novel roles for the PrrF sRNAs in the P. aeruginosa iron sparing response and pathogenesis.\n\nAUTHOR SUMMARYIron is central for the metabolism of almost all microbial pathogens, and as such this element is sequestered by the host innate immune system to restrict microbial growth. Defining the response of microbial pathogens to iron starvation is therefore critical for understanding how pathogens colonize and propagate within the host. The opportunistic pathogen Pseudomonas aeruginosa, which causes significant morbidity and mortality in compromised individuals, provides an excellent model for studying this response due to its high requirement for iron yet well-documented ability to overcome iron starvation. Here we used label-free proteomics to investigate the P. aeruginosa iron starvation response, revealing a broad landscape of metabolic and metal homeostasis changes that have not previously been described. We further provide evidence that many of these processes are regulated through the iron responsive PrrF small regulatory RNAs, which are integral to P. aeruginosa iron homeostasis and virulence. These results demonstrate the power of proteomics for defining stress responses of microbial pathogens, and they provide the most comprehensive analysis to date of the P. aeruginosa iron starvation response.

microbiology↗

bioRxiv2018

Fast trial-by-trial fronto-parietal cortical dynamics of conflict detection and context updating in a flanker task

The traditional N2 and P3 components of the human event-related potential (ERP) have been associated with cognitive control. However, recent research has found that the traditional target P3 consists of a mixture of stimulus-locked, response-locked, and latency variable P3-like positivities that can be functionally and topographically dissociated from one another. The current study aimed to extend previous results by examining target N2 and P3-like subcomponents indexing conflict detection and context updating at both low- and high-order levels in the neural hierarchy during control of target detection in a flanker task. Electroencephalographic (EEG) signals were recorded from 45 young adults while they completed a hybrid go/nogo flanker task, and Residue Iteration Decomposition (RIDE) was applied to functionally dissociate these peaks and establish their roles in conflict detection and context updating. Frequentist and Bayesian analyses showed a stimulus-locked frontal N2 revealing early conflict detection and fast categorization of nogo, congruous and incongruous trials, resulting in subsequent frontal P3-like activity (high-order context updating) elicited by infrequent nogo trials in the latency-variable RIDE cluster, and by the perceptually difficult incongruous trials in the response-locked cluster. In turn, the perceptually easier and more frequent congruous trials did not elicit frontal P3-like activity, although all trial types did elicit parietally distributed P3-like activity (low-order context updating), mostly within the latency-variable cluster. These novel findings support the presence of up to three distinct high-order task-set units regulating performance in our flanker task, as indexed by split-second, dynamic information transmission across frontal and parietal scalp regions.

neuroscience↗