Biology subjects

Mansfield, A.

Publications and source records attributed to Mansfield, A..

13 recordsLinked to original sources

bioRxiv2026

Temporal RNA splicing dysregulation in a human multicellular model of C9orf72 ALS

Amyotrophic lateral sclerosis (ALS) is a complex and heterogenous disease, comprising of familial and sporadic forms, numerous genetic mutations, and a wide range of affected cell types and proposed dysregulated processes. While the usage of in vitro cell cultures, mouse models, and postmortem patient tissue have advanced our understanding of ALS disease mechanisms, the temporal progression of the disease and how early molecular changes evolve remain poorly understood. Here, we establish human spinal cord organoids (hSpO) derived from C9orf72 patient induced pluripotent stem cells (C9-ALS hiPSCs) as a platform to model longitudinal changes across the disease trajectory. We show that C9-ALS hSpO recapitulate hallmark C9orf72-related pathologies, increased cell death, and progressive neuronal dysfunction. We further identify RNA splicing dysregulation as an early and persistent feature of C9-ALS, with splicing signatures in hSpO closely mirroring those observed in postmortem patient tissue. Finally, prediction of RNA binding proteins (RBPs) that induce early splicing changes in C9-ALS reveals signatures consistent with a broad RBP network dysfunction. Together, this work establishes hSpO as an in vitro system for investigating early disease mechanisms of ALS in a human multicellular context and highlights dysregulated events that precede cell death.

neuroscience↗

bioRxiv2026

The tilt board task as an internally valid practice-transfer paradigm for stabilometer balance assessments

Practice-transfer paradigms are central to motor learning research, yet dynamic balance lacks standardized, internally valid practice-transfer task pairings. This study evaluated whether a mediolateral tilt board can serve as a valid transfer task for stabilometer-based balance assessment. Sixteen healthy young adults (20-35 years) completed a single session consisting of two 40-second trials on a mediolateral stabilometer and two 40-second trials on a mediolateral tilt board. Participants aimed to keep each platform horizontal during each trial. Performance outcomes were derived from platform deviation angle. Neuromuscular outcomes were derived from surface EMG of bilateral gluteus medius, vastus lateralis, and vastus medialis, including muscle synergy structure, bilateral co-activation index, RMS amplitude of muscle activation, and strategy ratios (hip-to-knee and asymmetry metrics). Between-task associations were assessed using Spearman correlations. Cross-task muscle synergy similarity was high (mean cosine similarity = 0.915 {+/-} 0.044) and close to within-task trial-to-trial similarity, indicating preserved modular coordination across devices. Performance metrics were moderately to strongly correlated between tasks (RMS deviation angle: {rho} = 0.621, p = 0.0089; time-in-balance: {rho} = 0.668, p = 0.0036). EMG-derived strategy metrics also correlated significantly across tasks, including bilateral co-activation ({rho} = 0.688, p = 0.0023), hip-to-knee ratio ({rho} = 0.765, p = 0.0003), hip asymmetry ratio ({rho} = 0.688, p=0.0023), and knee asymmetry ratio ({rho} = 0.679, p = 0.0028). In contrast, EMG RMS amplitude did not correlate across tasks ({rho} = -0.044, p = 0.873), suggesting task-specific gain of activation magnitude. Stabilometer and tilt board tasks shared a similar coordination structure and showed a high correlation in balance performance and neuromuscular strategy, supporting the tilt board as an internally valid transfer task for stabilometer-based dynamic balance paradigms. Similarity of tasks appears strongest at the level of modular control and strategy organization, with device-specific gain scaling of activation amplitude.

neuroscience↗

bioRxiv2025

Determining perception thresholds of young adults to small continuous moving platform perturbations

Detecting external disturbances is vital for maintaining balance, as corrective actions are initiated to prevent falls. Quantifying peoples ability to perceive such disturbances improves our understanding of how balance is maintained. This study aims to: 1) quantify healthy young adults ability to perceive external perturbations while balancing on a stabilometer, and 2) understand the relationship between balance performance and perturbation magnitude relative to participants perception threshold. Participants (n=22; 20-35 years) completed a multiple staircase protocol. While standing on a stabilometer mounted on a moving platform, they attempted to keep it horizontal during 10-second trials with small continuous perturbations. After each trial, participants were asked whether they perceived the platform movement. Perturbation magnitudes were adjusted for the next trial based on their response. This process continued for each staircase until the termination criteria were met, at which point participants individual perception threshold was determined. Participants then performed ten 40-second trials on the stabilometer, two trials in each condition: without perturbation, perturbation at the 100%, 80%, and 50% of the individuals perception threshold, and the pilot studys minimum threshold. Balance performance was defined as time-in-balance ratio and RMS deviation angle from horizontal. Perception thresholds varied significantly between participants individuals, with an RMS acceleration ranging from 2.67 and 12.80 cm/s2. The results showed that perturbation magnitude has a significant correlation with variability in deviation angle (R=0.24, p=0.0038). The results suggest that some participants can perceive very small perturbations during a challenging balance task. Subthreshold perturbations, although very small, can influence balance performance. NEW & NOTEWORTHYTo our knowledge, this is the first study to quantitatively measure the conscious perception threshold of platform perturbations while doing a balancing task. We found that young healthy adults with little similar prior experience in tasks close to stabilameter balancing task can detect small platform perturbations while doing such challenging task. The results also showed that platform perturbations below conscious threshold can influence the balance performance on the stabilometer.

neuroscience↗

bioRxiv2025

Validity of measures of reactive balance training intensity

Intensity is a key component of exercise prescription. However, balance training intensity is not well defined. Consequently, balance training studies often do not report exercise intensity, which hinders implementing these interventions and developing exercise guidelines. This study aimed to validate measures of reactive balance training intensity. Healthy young (n=16) and older (n=15) adults experienced moving platform balance perturbations of varying magnitudes. Candidate intensity measures were: number of reactive steps; centre of mass displacement, velocity, and acceleration, and margin of stability 100 ms post-perturbation; peak electrodermal response; and OMNI Perceived Exertion Scale and Balance Intensity Scale scores. Correlations were examined between perturbation magnitude and candidate intensity measures. We also compared candidate intensity measures between backward- and forward-fall perturbations and between age groups using generalized linear mixed models. Peak centre of mass acceleration 100 ms after the perturbation was significant positively correlated with perturbation magnitude, with no significant age-group or direction effects, suggesting that this is a valid measure of absolute perturbation intensity. Number of reactive steps, peak electrodermal response, and OMNI Perceived Exertion Scale were significantly positively correlated with perturbation magnitude, and were significantly higher for backward-fall compared with forward fall perturbations and for older adults compared to younger adults at the same magnitude, suggesting that these are valid measures of relative perturbation intensity. These measures could be used to prescribe and report intensity of reactive balance training in future studies.

neuroscience↗

bioRxiv2025

The impact of perturbation intensity schedule on improvements in reactive balance control in young adults: an experimental study

BackgroundReactive balance training (RBT) uses unanticipated perturbations to improve balance reactions and prevent falls. Intensity and predictability of perturbations may affect the generalizability of RBT, but their relative contributions remain unclear. This study aimed to compare the effects of three RBT schedules with differing intensity and predictability on participants balance recovery following untrained perturbations, and to determine perceived difficulty and challenge of the training schedules. MethodsParticipants were 36 healthy young adults (20-35 years). Participants were randomly assigned to one of three RBT intensity schedules (fixed high intensity, low-to-high intensity, and variable intensity). Training took place on a motion platform that delivered perturbations in varying directions (forward, backward, left, and right) and intensities across five trial blocks. Balance reactions (number of recovery steps) pre- and post-training, and electrodermal responses, and perceived difficulty during training were collected. Statistical analyses compared post-training outcomes between training groups, controlling for the baseline value. ResultsParticipants took fewer steps and decreased the proportion of multi-step reactions pre- to post-training (p<0.0001), with no significant between-group differences. Perceived exertion decreased significantly across training blocks in the fixed-high group and increased significantly in the low-to-high group. Electrodermal responses declined across all groups between training blocks 1 and 3 (p=0.017). ConclusionsImprovements in step reactions to untrained perturbations did not differ between training groups, highlighting the importance of multi-directional variability over specific intensity schedules for enhancing balance recovery.

neuroscience↗

bioRxiv2024

Senescent fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity

Senescence has been demonstrated to either inhibit or promote tumorigenesis. Resolving this paradox requires spatial mapping and functional characterization of senescent cells in the native tumor niche. Here, we identified senescent p16Ink4a+ cancer-associated fibroblasts with a secretory phenotype that promotes fatty acid uptake and utilization by aggressive lung adenocarcinoma driven by Kras and p53 mutations. Furthermore, rewiring of lung cancer metabolism by p16Ink4a+ cancer- associated fibroblasts also altered tumor cell identity to a highly plastic/dedifferentiated state associated with progression in murine and human LUAD. Our ex vivo senolytic screening platform identified XL888, a HSP90 inhibitor, that cleared p16Ink4a+ cancer- associated fibroblasts in vivo. XL888 administration after establishment of advanced lung adenocarcinoma significantly reduced tumor burden concurrent with the loss of plastic tumor cells. Our study identified a druggable component of the tumor stroma that fulfills the metabolic requirement of tumor cells to acquire a more aggressive phenotype.

cancer biology↗

bioRxiv2023

A deep catalog of protein-coding variation in 985,830 individuals

Coding variants that have significant impact on function can provide insights into the biology of a gene but are typically rare in the population. Identifying and ascertaining the frequency of such rare variants requires very large sample sizes. Here, we present the largest catalog of human protein-coding variation to date, derived from exome sequencing of 985,830 individuals of diverse ancestry to serve as a rich resource for studying rare coding variants. Individuals of African, Admixed American, East Asian, Middle Eastern, and South Asian ancestry account for 20% of this Exome dataset. Our catalog of variants includes approximately 10.5 million missense (54% novel) and 1.1 million predicted loss-of-function (pLOF) variants (65% novel, 53% observed only once). We identified individuals with rare homozygous pLOF variants in 4,874 genes, and for 1,838 of these this work is the first to document at least one pLOF homozygote. Additional insights from the RGC-ME dataset include 1) improved estimates of selection against heterozygous loss-of-function and identification of 3,459 genes intolerant to loss-of-function, 83 of which were previously assessed as tolerant to loss-of-function and 1,241 that lack disease annotations; 2) identification of regions depleted of missense variation in 457 genes that are tolerant to loss-of-function; 3) functional interpretation for 10,708 variants of unknown or conflicting significance reported in ClinVar as cryptic splice sites using splicing score thresholds based on empirical variant deleteriousness scores derived from RGC-ME; and 4) an observation that approximately 3% of sequenced individuals carry a clinically actionable genetic variant in the ACMG SF 3.1 list of genes. We make this important resource of coding variation available to the public through a variant allele frequency browser. We anticipate that this report and the RGC-ME dataset will serve as a valuable reference for understanding rare coding variation and help advance precision medicine efforts.

genetics↗

bioRxiv2022

Do we perform as well as we think we do? A systematic scoping review of self-evaluation of upper-extremity motor performance

The ability to self-evaluate motor performance or estimate performance errors is beneficial for motor learning or relearning in the context of neurologic injury. Some evidence suggests those with injury like stroke may be unable to accurately self-evaluate their performance; however, it is unclear if individuals who are absent of injury are accurate in this domain. We aimed to investigate the accuracy of self-evaluation and potential influencing factors by conducting a systematic search to identify literature involving the self- and objective-evaluation of upper-extremity motor tasks. Twenty-three studies satisfied inclusion criteria. Data revealed a moderate positive correlation between self- and objective evaluations across a variety of tasks, from trivial button pressing to specialized surgical suturing. Both under- and overestimation of performance was found across the papers. Key factors identified to influence the accuracy of self-evaluation were the task purpose, familiarity, difficulty, and whether an individual received a demonstration. This review identified some limitations in this field of research. Most notably, we found that very few studies have investigated the accuracy of self-evaluation of motor performance with the primary goal of comparison to objective performance. Many studies reported the data but did not make direct statistical comparisons. Moreover, due to inconsistencies between how self and objective-evaluations were conducted, we argue that in this area of investigation self-evaluation tools need to replicate the objective evaluation method, or at minimum the self-evaluation tool should ask questions specific to the construct of performance that is being measured objectively.

neuroscience↗

bioRxiv2020

Does increased gait variability improve stability when faced with an expected balance perturbation during treadmill walking?

BackgroundCurrently, there is uncertainty as to whether movement variability is errorful or exploratory. Research questionThis study aimed to determine if gait variability represents exploration to improve stability. We hypothesized that 1) spatiotemporal gait features will be more variable prior to an expected perturbation than during unperturbed walking, and 2) increased spatiotemporal gait variability pre-perturbation will correlate with improved stability post-perturbation. MethodsSixteen healthy young adults completed 15 treadmill walking trials within a motion simulator under two conditions: unperturbed and expecting a perturbation. Participants were instructed not to expect a perturbation for unperturbed trials, and to expect a single transient medio-lateral balance perturbation for perturbed trials. Kinematic data were collected during the trials. Twenty steps were recorded post-perturbation. Unperturbed and pre-perturbation gait variabilities were defined by the short- and long-term variabilities of step length, width, and time, using 100 steps from pre-perturbation and unperturbed trials. Paired t-tests identified between-condition differences in variabilities. Stability was defined as the number of steps to centre of mass restabilization post-perturbation. Multiple regression analyses determined the effect of pre-perturbation variability on stability. ResultsLong-term step width variability was significantly higher pre-perturbation compared to unperturbed walking (mean difference=0.28cm, p=0.0073), with no significant differences between conditions for step length or time variabilities. There was no significant relationship between pre-perturbation variability and post-perturbation restabilization. SignificanceIncreased pre-perturbation step width variability was neither beneficial nor detrimental to stability. However, the increased variability in medio-lateral foot placement suggests that participants adopted an exploratory strategy in anticipation of a perturbation.

neuroscience↗

bioRxiv2019

The effects of postural threat induced by a virtual environment on performance of a walking balance task.

Rapid motor learning may occur in situations where individuals perceive a threat of injury if they do not perform a task well. This rapid motor learning may be facilitated by improved motor performance and, consequently, more errorless practice. As a first step towards understanding the role of perceived threat on rapid motor learning, the purpose of this study was to determine how performance of a motor task is affected in situations where perceived threat of injury is high. We hypothesized that perceived threat of injury in a virtual environment would result in improved performance of a walking task (i.e., walking on a narrow beam). Results demonstrated that increased perceived threat of injury yielded slightly greater, but not statistically significant, balance performance in virtual environments (median percentage of successful steps: 78.8%, 48.3%, and 55.2% in the real low-threat, virtual low-threat, and virtual high-threat environments, respectively). These results may be partially attributed to habituation to threat over time and practice. If implemented carefully, virtual reality technology can be an effective tool for investigating walking balance in environments that are perceived as threatening.

physiology↗

bioRxiv2019

Does the margin of stability measure predict stability of gait with a constrained base of support?

This study aimed to determine the validity of the centre of mass position (COM) position and extrapolated COM (XCOM), relative to the base of support, for predicting stability during a walking task where the base of support is constrained. Nine young healthy participants walked on a narrow beam. Three-dimensional motion capture was used to calculate the COM and XCOM relative to the base of support. Steps were classified as having either the COM or XCOM inside or outside the base of support, and were classified as successful (stable - foot placed on the beam) or failed (unstable - foot stepped off the beam). If the COM or XCOM are valid measures of stability, they should be within the base of support for successful steps and outside the base of support for failed steps. Classifying the COM and XCOM inside or outside the base of support correctly predicted successful or failed steps in 69% and 58% of cases, respectively. When the COM or XCOM were outside the base of support, walking faster seemed to help participants to maintain stability. The further the COM or XCOM were outside the base of support during a successful step, the more likely participants were to fail on a subsequent step. The results of this study suggest that both COM and XCOM are valid measures of stability during a beam walking task, but that classifying COM and XCOM as inside or outside the base of support may be over-simplistic.

bioengineering↗

bioRxiv2018

B7-H1(PD-L1) confers chemoresistance through ERK and p38 MAPK pathway in tumor cells

Development of resistance to chemotherapy and immunotherapy is a major obstacle in extending the survival of patients with cancer. Although several molecular mechanisms have been identified that can contribute to chemoresistance, the role of immune checkpoint molecules in tumor chemoresistance remains underestimated. It has been recently observed that overexpression of B7-H1(PD-L1) confers chemoresistance in human cancers, however the underlying mechanisms are unclear. Here we show that the development of chemoresistance depends on the increased activation of ERK pathway in tumor cells overexpressing B7-H1. Conversely, B7-H1 deficiency renders tumor cells susceptible to chemotherapy in a cell-context dependent manner through activation of the p38 MAPK pathway. B7-H1 in tumor cells associates with the catalytic subunit of a DNA-dependent serine / threonine protein kinase (DNA-PKcs). DNA-PKcs is required for the activation of ERK or p38 MAPK in tumors expressing B7-H1, but not in B7-H1 negative or B7-H1 deficient tumors. Ligation of B7-H1 by anti-B7-H1 monoclonal antibody (H1A) increased the sensitivity of human triple negative breast tumor cells to cisplatin therapy in vivo. Our results suggest that B7-H1(PD-L1) expression in cancer cells modifies their chemosensitivity towards certain drugs and targeting B7-H1 intracellular signaling pathway is a new way to overcome cancer chemoresistance.

cancer biology↗

bioRxiv2018

xAtlas: Scalable small variant calling across heterogeneous next-generation sequencing experiments

MotivationThe rapid development of next-generation sequencing (NGS) technologies has lowered the barriers to genomic data generation, resulting in millions of samples sequenced across diverse experimental designs. The growing volume and heterogeneity of these sequencing data complicate the further optimization of methods for identifying DNA variation, especially considering that curated highconfidence variant call sets commonly used to evaluate these methods are generally developed by reference to results from the analysis of comparatively small and homogeneous sample sets.\n\nResultsWe have developed xAtlas, an application for the identification of single nucleotide variants (SNV) and small insertions and deletions (indels) in NGS data. xAtlas is easily scalable and enables execution and retraining with rapid development cycles. Generation of variant calls in VCF or gVCF format from BAM or CRAM alignments is accomplished in less than one CPU-hour per 30x short-read human whole-genome. The retraining capabilities of xAtlas allow its core variant evaluation models to be optimized on new sample data and user-defined truth sets. Obtaining SNV and indels calls from xAtlas can be achieved more than 40 times faster than established methods while retaining the same accuracy.\n\nAvailabilityFreely available under a BSD 3-clause license at https://github.com/jfarek/xatlas.\n\nContactfarek@bcm.edu\n\nSupplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗