Biology subjects

Horton, C.

Publications and source records attributed to Horton, C..

6 recordsLinked to original sources

bioRxiv2025

Uncovering senescent fibroblast heterogeneity connects DNA damage response to idiopathic pulmonary fibrosis

Cellular senescence is a largely heterogeneous state of cell stress that deleteriously accumulates with age. Many types of heterogeneity in senescence have been described; however, cellular senescence within the same cell type has only started to be documented. Here, we show primary, human lung fibroblasts from donors who are healthy or diagnosed with idiopathic pulmonary fibrosis (IPF) exhibit a subtle form of heterogeneity over time after DNA damage. Moreover, senescent IPF lung fibroblasts display a dysregulated transcriptional-protein DNA damage response (DDR). Weighted gene correlation network analysis (WGCNA) reveals unique and known targets linking senescent IPF lung fibroblast heterogeneity to genes associated with DNA damage and repair, cytokine and chemokine responses, and extracellular matrix (ECM) signaling. We combine our healthy and IPF senescent gene expression signatures to develop a novel gene set of senescence-associated genes that identify disease-relevant cells in human single-cell RNA-seq (scRNA-seq) data. Collectively, our results uncover human-relevant senescence signatures, highlight IPF-specific DDR, cytokine and chemokine, and ECM targets, and expand our understanding of how a dysregulated DDR contributes to senescent cell heterogeneity in IPF.

cell biology↗

bioRxiv2024

Goal-directed action preparation in humans entails a mixture of corticospinal neural computations

The seemingly effortless ability of humans to transition from thinking about actions to initiating them relies on sculpting corticospinal output from primary motor cortex. This study tested whether canonical additive and multiplicative neural computations, well-described in sensory systems, generalize to the corticospinal pathway during human action preparation. We used non-invasive brain stimulation to measure corticospinal input-output across varying action preparation contexts during instructed-delay finger response tasks. Goal-directed action preparation was marked by increased multiplicative gain of corticospinal projections to task-relevant muscles and additive suppression of corticospinal projections to non-selected and task-irrelevant muscles. Individuals who modulated corticospinal gain to a greater extent were faster to initiate prepared responses. Our findings provide physiological evidence of combined additive suppression and gain modulation in the human motor system. We propose these computations support action preparation by enhancing the contrast between selected motor representations and surrounding background activity to facilitate response selection and execution. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/602530v4_figa1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@9f2444org.highwire.dtl.DTLVardef@5f6eforg.highwire.dtl.DTLVardef@196f41corg.highwire.dtl.DTLVardef@1746035_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOC_FLOATNO Goal-directed action preparation shapes corticospinal output across selected, nonselected, and task-irrelevant motor representations. This study examined whether additive and multiplicative neural computations, common in sensory systems, occur within the corticospinal pathway during action preparation. We probed corticospinal input-output during the performance of various instructed-delay response tasks by applying a range of transcranial magnetic stimulation (TMS) intensities (input) over the primary motor cortex and measuring the resultant motor-evoked potentials (output) from the hand. We found that goal-directed action preparation increases corticospinal gain multiplicatively in task-relevant motor representations while additively suppressing nonselected and irrelevant representations. Greater gain modulation predicted faster responses, highlighting how these computations can enhance signal-to-noise (SNR) to enable efficient action selection and execution in the human motor system. C_FIG Key pointsO_LINeural computations determine what information is transmitted through brain circuits. C_LIO_LIWe investigated whether the motor system uses computations similar to those observed in sensory systems by noninvasively stimulating the corticospinal pathway in humans during goal-directed action preparation. C_LIO_LIWe discovered physiological evidence that corticospinal projections to behaviorally relevant muscles exhibit nonlinear gain computations, while projections to behaviorally irrelevant muscles exhibit linear suppression. C_LIO_LIOur findings suggest that certain computational principles generalize to the human motor system and serve to enhance the contrast between relevant and background neural activity. C_LIO_LIThese results indicate that neural computations during goal-directed action preparation may support motor control by increasing signal-to-noise within the corticospinal pathway. C_LI

neuroscience↗

bioRxiv2024

Corticospinal excitability at rest outside of a task does not differ from task intertrial intervals in healthy adults

Human corticospinal excitability modulates during movement, when muscles are active, but also at rest, when muscles are not active. These changes in resting motor system excitability can be transient or longer lasting. Evidence from transcranial magnetic stimulation (TMS) studies suggests even relatively short periods of motor learning on the order of minutes can have lasting effects on resting corticospinal excitability. Whether individuals are able to return corticospinal excitability to out-of-task resting levels during the intertrial intervals of behavioral tasks that do not include an intended motor learning component is an important question. Here, in twenty-six healthy young adults, we used single-pulse TMS and electromyography (EMG) to measure motor evoked potentials (MEPs) during two different resting contexts: 1) intertrial intervals of a choice-reaction time task, and 2) outside the task. In both contexts, five TMS intensities were used to evaluate possible differences in recruitment of corticospinal output. We hypothesized resting state excitability would be greater during intertrial intervals than out-of-task rest, reflected in larger MEP amplitudes. Contrary to our hypothesis, we observed no significant difference in MEP amplitudes between out-of-task rest and in-task intertrial intervals, and instead found evidence of equivalence, indicating that humans are able to return to a stable motor resting state within seconds after a response. These data support the interpretation that rest is a uniform motor state in the healthy nervous system. In the future, our data may be a useful reference for motor disorder populations with an impaired ability to return to rest.

neuroscience↗

bioRxiv2023

Assigning credit where it's due: An information content score to capture the clinical value of Multiplexed Assays of Variant Effect

BackgroundA variant can be pathogenic or benign with relation to a human disease. Current classification categories from benign to pathogenic reflect a probabilistic summary of current understanding. A primary metric of clinical utility for multiplexed assays of variant effect (MAVE) is the number of variants that can be reclassified from uncertain significance (VUS). However, we hypothesized that this measure of utility underrepresents the information gained from MAVEs and that an information theory approach which includes data that does not reclassify variants will better reflect true information gain. We used this information theory approach to evaluate the information gain, in bits, for MAVEs of BRCA1, PTEN, and TP53. Here, one bit represents the amount of information required to completely classify a single variant starting from no information. ResultsBRCA1 MAVEs produced a total of 831.2 bits of information, 6.58% of the total missense information in BRCA1 and a 22-fold increase over the information that only contributed to VUS reclassification. PTEN MAVEs produced 2059.6 bits of information which represents 32.8% of the total missense information in PTEN and an 85-fold increase over the information that contributed to VUS reclassification. TP53 MAVEs produced 277.8 bits of information which represents 6.22% of the total missense information in TP53 and a 3.5-fold increase over the information that contributed to VUS reclassification. ConclusionsAn information content approach will more accurately portray information gained through MAVE mapping efforts than counting the number of variants reclassified. This information content approach may also help define the impact of modifying information definitions used to classify many variants, such as guideline rule changes.

genetics↗

bioRxiv2020

Modulation of the canonical Wnt activity by androgen signaling in prostate epithelial basal stem cells

Both the canonical Wnt signaling and androgen signaling are important factors regulating prostate organogenesis. How these two pathways crosstalk to regulate prostate stem cell functions remain unclear. Here, we show that while canonical Wnt activity is required for prostate basal stem cell multipotency in vivo, ectopic Wnt activity does not promote basal-to-luminal cell differentiation. We provide evidence that androgen signaling may keep Wnt activity in check. In prostate organoid culture from basal cells, dihydrotestosterone (DHT) antagonizes R-spondin-stimulated organoid growth in a concentration-dependent manner. Molecular analyses of organoids under different treatment conditions showed that androgen signaling down-regulated the expressions of a Wnt reporter as well as many Wnt target genes. Pathway analysis and gene set enrichment analysis of organoid RNA-seq data also revealed the canonical Wnt signaling as a key pathway distinguishing organoids treated with or without DHT. Notably, DHT treatment enhanced AR and {beta}-catenin binding in the nuclei of prostate organoids, providing possible mechanistic clues. Our results reveal a critical role of AR signaling in modulating canonical Wnt activity in prostate basal cells to regulate their multipotency.

developmental biology↗

bioRxiv2018

MYC Functions as a Switch for Natural Killer Cell-Mediated Immune Surveillance of Lymphoid Malignancies

The MYC oncogene drives T and B lymphoid malignancies, including Burkitts lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Using CyTOF, we demonstrate a systemic reduction in natural killer (NK) cell-mediated surveillance in SR-tTA/Tet-O-MYCON mice bearing MYC-driven T-lymphomas, due to an arrest in NK cell maturation. Inactivation of lymphoma-intrinsic MYC releases the brakes on NK maturation restoring NK homeostasis. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.\n\nAbbreviations

cancer biology↗