Biology subjects

Munoz, D. P.

Publications and source records attributed to Munoz, D. P..

8 recordsLinked to original sources

bioRxiv2025

Learning to blink strategically is crucial to performance in a predictable saccade task and varies across the lifespan

Humans blink their eyes 16-20 times each minute to spread tear film on the cornea, representing a substantial amount of waking time when ones eyes are closed. These spontaneous blinks are strategically timed to prioritize the processing of important visual input, balancing both stimulus characteristics and personal goals. Until now, the learning process underlying optimal blink timing has not been investigated in detail. Here, we present video-based eye-tracking data from 703 healthy participants (aged 5-91 years, 470 female) performing a structured interleaved pro-/anti-saccade task, in which we previously found that blink suppression occurs in anticipation of visual stimulus appearance (Pitigoi et al., 2024). Our goals are to understand (1) how participants modify their blink timing according to the temporal contingencies of the task; (2) whether the capacity to optimize blink timing impacts performance; and (3) whether this pattern varies with age. We found that participants quickly and strategically modified their blink distribution to optimize task performance. Blink probability decreased in periods that would compromise anti-saccade execution and increased when visual input was less critical. We also found significant differences in blink patterns and adaptive ability based on cognitive control capacity (indicated by participants anti-saccade error rates). Furthermore, we demonstrated that blink optimization improves gradually from childhood to early adulthood, before declining with advanced age. This supports a possible link between regulation of blink behavior and age-related changes in learning capacity and inhibitory control across the lifespan.

neuroscience↗

bioRxiv2024

Super-enhancer profiling reveals ThPOK/ZBTB7B, a CD4+ cell lineage commitment factor, as a master regulator that restricts breast cancer cells to a luminal non-migratory phenotype

Despite efforts to understand breast cancer biology, metastatic disease remains a clinical challenge. Identifying suppressors of breast cancer progression and mechanisms of transition to more invasive phenotypes could provide game changing therapeutic opportunities. Transcriptional deregulation is central to all malignancies, highlighted by the extensive reprogramming of regulatory elements that underlie oncogenic programs. Among these, super-enhancers (SEs) stand out due to their enrichment in genes controlling cancer hallmarks. To reveal novel breast cancer dependencies, we integrated the analysis of the SE landscape with master regulator activity inference for a series of breast cancer cell lines. As a result, we identified T-helper-inducing Poxviruses and Zinc-finger (POZ)/Kruppel-like factor (ThPOK, ZBTB7B), a CD4+ cell lineage commitment factor, as a breast cancer master regulator that is recurrently associated with a SE. ThPOK expression is highest in luminal breast cancer but is significantly reduced in the basal subtype. Manipulation of ThPOK levels in cell lines shows that its repressive function restricts breast cancer cells to an epithelial phenotype by suppressing the expression of genes involved in the epithelial-mesenchymal transition (EMT), WNT/{beta}-catenin target genes, and the pro-metastatic TGF{beta} pathway. Our study reveals ThPOK as a master transcription factor that restricts the acquisition of metastatic features in breast cancer cells.

cancer biology↗

bioRxiv2024

Main Sequence of Human Luminance-Evoked Pupil Dynamics

Pupil responses are commonly used to provide insight into visual perception, autonomic control, cognition, and various brain disorders. However, making inferences from pupil data can be complicated by nonlinearities in pupil dynamics and variability within and across individuals, which challenge the assumptions of linearity or group level homogeneity required for common analysis methods. In this study, we evaluated luminance evoked pupil dynamics in young healthy adults (N=10, 5:5 M:F, ages 19-25) by identifying nonlinearities, variability, and conserved relationships across individuals to improve the ability to make inferences from pupil data. We found a nonlinear relationship between final pupil diameter and luminance, linearized by considering the logarithm of luminance. Peak diameter change and peak velocity were nonlinear functions of log-luminance for constriction but not dilation responses. Across participants, curve fit parameters characterizing pupil responses as a function of luminance were highly variable, yet there was an across-participant linear correlation between overall pupil size and pupil gain (i.e. diameter change per unit log-luminance change). In terms of within-participant trial-by-trial variability, participants showed greater variability in final pupil size compared to constriction peak diameter change as a function of log-luminance. Despite the variability in stimulus-response metrics within and across participants, we found that all participants showed a highly stereotyped "main sequence" relationship between peak diameter change and peak velocity (independent of luminance). The main sequence relationship can be used to inform models of the neural control of pupil dynamics and as an empirical analysis tool to evaluate variability and abnormalities in pupil behaviour.

neuroscience↗

bioRxiv2022

A reversible SRC-relayed COX2-inflammatory program drives therapeutic resistance in BRAF(V600E) colorectal tumors

BRAFV600E mutation confers a poor prognosis in metastatic colorectal cancer (CRC) despite combinatorial targeted therapies based on the latest understanding of signaling circuitry. To identify parallel resistance mechanisms induced by BRAF/MEK/EGFR co-targeting, we used a high throughput kinase activity mapping platform. We found that SRC kinases are systematically activated in BRAFV600E CRC following targeted inhibition of BRAF {+/-} EGFR, and that coordinated targeting of SRC with BRAF {+/-} EGFR increases efficacy in vitro and in vivo. SRC drives resistance to BRAF {+/-} anti-EGFR therapy independently of ERK signaling by inducing transcriptional reprogramming via beta-catenin (CTNNB1). The EGFR-independent compensatory activation of SRC kinases is mediated by an autocrine prostaglandin E2-loop that can be blocked with cyclooxygenase-2 (COX2) inhibitors. Co-targeting of COX2 with BRAF+EGFR promotes durable suppression of tumor growth in patient-derived tumor xenograft (PDX) models. COX2 inhibition represents a novel drug-repurposing strategy to overcome therapeutic resistance in BRAFV600E CRC.

cancer biology↗

bioRxiv2022

Automated Analysis Pipeline for Extracting Saccade, Pupil, and Blink Parameters Using Video-Based Eye Tracking

The tremendous increase of video-based eye tracking has made it possible to collect data from thousands of participants. Traditional manual detection and classification procedures for saccades and trial categorization is not viable for the large data sets being collected. Additionally, high-speed video-based eye trackers now allow for the novel analysis of pupil responses and blink behavior. Here we present a detailed description of our pipeline for collecting data, storing data, organizing participant codes, and cleaning data, which are fairly lab-specific but nonetheless important precursory steps in establishing standardized pipelines. More importantly, we also include descriptions of the automated detection and classification of saccades, blinks, blincades (blinks occurring during saccades), and boomerang saccades (two saccades in opposite directions that occur almost simultaneously so that speed-based algorithms fail to split them), which are almost entirely task-agnostic and can be used on a wide variety of data. We additionally describe novel findings about post-saccadic oscillations, and provide a method to get more accurate estimates for end-points of saccades. Lastly, we describe the automated behavior classification for the Interleaved Pro- and Anti-Saccade Task (IPAST), a well-known task that probes voluntary and inhibitory control. This pipeline was evaluated using data collected from 592 human participants between 5 and 93 years of age, making it robust enough to handle large clinical patient data sets as well. In sum, this pipeline has been optimized to consistently handle large data sets obtained from diverse study cohorts (i.e., development, aging, clinical), and collected across multiple laboratory sites.

neuroscience↗

bioRxiv2021

Comparison of cerebrospinal fluid biomarkers relevant to neurodegenerative diseases in healthy cynomolgus and rhesus macaque monkeys

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSNon-human primates are important translational models of neurodegenerative disease. We characterized how species, sex, age, and site of sampling affected concentrations of key biomarkers of neurodegeneration. METHODSAmyloid-beta (A{beta}40, A{beta}42), tau (tTau, pTau), and neurofilament light (NFL) in CSF were measured in 82 laboratory-housed naive cynomolgus and rhesus macaques of both sexes. RESULTSA{beta}40, A{beta}42, and NFL were significantly higher in rhesus compared with cynomolgus macaques. tTau and NFL were higher in males. pTau was not affected by species or sex. Site of acquisition only affected NFL, with NFL being higher in CSF acquired from lumbar compared with cisterna magna puncture. DISCUSSIONNormative values for key neurodegeneration biomarkers were established for laboratory housed cynomolgus and rhesus macaque monkeys. Differences were observed as a function of species, sex and site of CSF acquisition that should be considered when employing primate models. Research In ContextO_LISystematic review: We reviewed reports characterizing CSF biomarkers of neurodegenerative diseases in non-human primates - an increasingly important model of disease - revealing that studies with laboratory housed macaque monkeys were of small sample size, with a paucity of data about how biomarkers varied as a function of species, sex, age, and site of acquisition. C_LIO_LIInterpretation: To address this gap, we collected CSF from 82 naive laboratory housed male and female macaques of two species and measured A{beta}40, A{beta}42, tTau, pTau, and NFL. In addition to providing normative statistics for concentrations of these biomarkers, we revealed various species and sex differences. C_LIO_LIFuture directions: Establishing normative values of biomarkers is an important step to the efficient development of cynomolgus and rhesus macaques as models of neurodegenerative disorders such as Alzheimers disease. Reference values reduce the need for large control groups by which to compare with disease model animals. C_LI

neuroscience↗

bioRxiv2021

Impulsivity and Emotional Dysregulation Predict Choice Behavior During a Competitive Multiplayer Game in Adolescents with Borderline Personality Disorder

Impulsivity and emotional dysregulation are two core features of borderline personality disorder (BPD), and the neural mechanisms recruited during mixed-strategy interactions overlap with frontolimbic networks that have been implicated in BPD. We investigated strategic choice patterns during the classic two-player game, Matching Pennies, where the most efficient strategy is to choose each option randomly from trial-to-trial to avoid exploitation by one's opponent. Twenty-seven female adolescents with BPD (mean age: 16 years) and twenty-seven age-matched female controls (mean age: 16 years) participated in an experiment that explored the relationship between strategic choice behavior and impulsivity in both groups and emotional dysregulation in BPD. Relative to controls, BPD participants showed fewer reinforcement learning biases, increased coefficient of variation in reaction times (CV), and more anticipatory decisions. A subset of BPD participants characterized by high levels of impulsivity and emotional dysregulation showed increased reward rate, increased entropy in choice patterns, decreased CV, and fewer anticipatory decisions relative to participants with lower indices, and emotion dysregulation mediated the relationship between impulsivity and CV in BPD. Finally, exploratory analyses revealed that increased vigilance to outcome was associated with higher reward rates, decreased variability in SRT, and fewer anticipatory decisions. In BPD, higher levels of emotion dysregulation corresponded to increased vigilance to outcome, and mediated its relationship with choice behavior. Together, our results suggest that impulsivity and emotional dysregulation contribute to variability in mixed-strategy decision-making in BPD, the latter of which may influence choice behavior by increasing attention to outcome information during the task.

neuroscience↗

bioRxiv2019

Ontario Neurodegenerative Disease Research Initiative (ONDRI): Structural MRI methods & outcome measures

The Ontario Neurodegenerative Research Initiative (ONDRI) is a 3 year multi-site prospective cohort study that has acquired comprehensive multiple assessment platform data, including 3T structural MRI, from neurodegenerative patients with Alzheimers disease, mild cognitive impairment, Parkinsons disease, amyotrophic lateral sclerosis, frontotemporal dementia, and cerebrovascular disease patients. This heterogeneous cross-section of patients with complex neurodegenerative and neurovascular pathologies pose significant challenges for standard neuroimaging tools. To effectively quantify regional measures of normal and pathological brain tissue volumes, the ONDRI neuroimaging platform implemented a semi-automated MRI processing pipeline that was able to address many of the challenges resulting from this heterogeneity. This paper describes the comprehensive neuroimaging pipeline methods used to generate regional brain tissue volumes & neurovascular markers.

neuroscience↗