Biology subjects

Martin, J. T.

Publications and source records attributed to Martin, J. T..

7 recordsLinked to original sources

bioRxiv2024

Binocular combination in the autonomic nervous system

Pupil diameters are regulated by the autonomic nervous system, which combines light signals across the eyes independently of the visual cortex. Distinct classes of retinal photoreceptor are involved in this process, with cones and rods driving the initial constriction and intrinsically photosensitive retinal ganglion cells main-taining diameter over prolonged time periods. We investigated binocular combination by targeting different photoreceptor pathways using a novel binocular multiprimary system to modulate the input spectra via silent substitution. At the first harmonic of the modulation frequency, luminance and S-cone responses showed strong binocular facilitation, and weak interocular suppression. Melanopsin responses were invariant to the number of eyes stimulated. The L-M pathway involved binocular inhibition, whereby responses to binocular stimulation were weaker than for monocular stimulation. The second harmonic involved strong interocular suppression in all pathways, but with some evidence of binocular facilitation. Our results are consistent with a computational model of binocular signal combination (implemented in a Bayesian hierarchical framework), in which the weight of interocular suppression differs across pathways. We also find pathway differences in response phase, consistent with different lag times for phototransduction. These results provide evidence that binocular interactions in the pupillary pathway differ across photoreceptor-directed modulations and across harmonic components of the response.

neuroscience↗

bioRxiv2023

PySilSub: An open-source Python toolbox for implementing the method of silent substitution in vision and nonvisual photoreception research

The normal human retina contains several classes of photosensitive cell--rods for low-light vision, three cone classes for daylight vision, and intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing melanopsin for non-image-forming functions including pupil control, melatonin suppression and circadian photoentrainment. The spectral sensitivities of the photoreceptors overlap significantly, which means that most lights will stimulate all photoreceptors, to varying degrees. The method of silent substitution is a powerful tool for stimulating individual photoreceptor classes selectively and has found much use in research and clinical settings. The main hardware requirement for silent substitution is a spectrally calibrated light stimulation system with at least as many primaries as there are photoreceptors under consideration. Device settings that will produce lights to selectively stimulate the photoreceptor(s) of interest can be found using a variety of analytic and algorithmic approaches. Here we present PySilSub (https://github.com/PySilentSubstitution/pysilsub), a novel Python package for silent substitution featuring flexible object-oriented support for individual colorimetric observer models (including human and mouse observers), multi-primary stimulation devices, and solving silent substitution problems with linear algebra and constrained numerical optimisation. The toolbox is registered with the Python Package Index and includes example data sets from various multi-primary systems. We hope that PySilSub will facilitate the application of silent substitution in research and clinical settings.

neuroscience↗

bioRxiv2023

LCP1 Regulates Cell Motility in Chondrosarcoma and Correlates with Metastatic Potential and Poor Patient Outcomes

Chondrosarcoma (CSA) is the second most common primary malignancy of bone, whose aggressive potential and chemo-resistant nature result in extremely poor outcomes in patients with advanced disease. Grading and prognostication of these tumors remain a significant challenge for pathologists, and medical oncologists have no effective therapies to prevent or treat metastatic disease. In the present study, we sought to explore the pathogenesis and aggressive progression of chondrosarcoma by comparing gene expression differences from metastasizing and non-metastasizing CSA tumors. We hypothesized that metastasizing tumors have inherent differences that may be attributed to the dysregulation of specific oncogenic cell signaling pathways. RNA-Seq analysis from patient-derived low-passage cell lines of metastasizing and non-metastasizing tumors pinpointed the gene LCP1 (lymphocyte cytosolic protein 1) as upregulated in CSA cells from metastasizing tumors. Analysis of a large clinical cohort of CSA demonstrated that increased expression of LCP1 correlated with poor patient survival. In vitro analyses confirmed the ability of LCP1 to promote migration and invasion of CSA cells. These data support the key role of LCP1 on metastatic potential and poor prognosis in CSA. In conclusion, we confirm the ability of LCP1 to drive metastatic behavior and correlate with poor outcomes in patients.

cancer biology↗

bioRxiv2021

Pupillometry and the vigilance decrement: Task-evoked but not baseline pupil measures reflect declining performance in visual vigilance tasks

Baseline and task-evoked pupil measures are known to reflect the activity of the nervous systems central arousal mechanisms. With the increasing availability, affordability and flexibility of video-based eye tracking hardware, these measures may one day find practical application in real-time biobehavioral monitoring systems to assess performance or fitness for duty in tasks requiring vigilant attention. But real-world vigilance tasks are predominantly visual in their nature and most research in this area has taken place in the auditory domain. Here we explore the relationship between pupil size--both baseline and task-evoked--and behavioral performance measures in two novel vigilance tasks requiring visual target detection: 1) a traditional vigilance task involving prolonged, continuous, and uninterrupted performance (n = 28), and 2) a psychomotor vigilance task (n = 25). In both tasks, behavioral performance and task- evoked pupil responses declined as time spent on task increased, corroborating previous reports in the literature of a vigilance decrement with a corresponding reduction in task-evoked pupil measures. Also in line with previous findings, baseline pupil size did not show a consistent relationship with performance measures. We discuss our findings considering the adaptive gain theory of locus coeruleus function and question the validity of the assumption that baseline (prestimulus) pupil size and task-evoked (poststimulus) pupil measures correspond to the tonic and phasic firing modes of the LC.

neuroscience↗

bioRxiv2021

PyPlr: A versatile, integrated system of hardware and software for researching the human pupillary light reflex

We introduce PyPlr--a versatile, integrated system of hardware and software to support a broad spectrum of research applications concerning the human pupillary light reflex (PLR). PyPlr is a custom Python library for integrating a research-grade video-based eye-tracker system with a light source and streamlining stimulus design, optimisation and delivery, device synchronisation, and extraction, cleaning, and analysis of pupil data. We additionally describe how full-field, homogenous stimulation of the retina can be realised with a low-cost integrating sphere that serves as an alternative to a more complex Maxwellian view setup. Users can integrate their own light source, but we provide full native software support for a high-end, commercial research-grade 10-primary light engine that offers advanced control over the temporal and spectral properties of light stimuli as well as spectral calibration utilities. Here, we describe the hardware and software in detail and demonstrate its capabilities with two example applications: 1) pupillometer-style measurement and parametrisation of the PLR to flashes of white light, and 2) comparing the post-illumination pupil response (PIPR) to flashes of long and short-wavelength light. The system holds promise for researchers who would favour a flexible approach to studying the PLR and the ability to employ a wide range of temporally and spectrally varying stimuli, including simple narrowband stimuli.

physiology↗

bioRxiv2020

Targeting HIV Env immunogens to B cell follicles in non-human primates through immune complex or protein nanoparticle formulations

Following immunization, high affinity antibody responses develop within germinal centers (GCs), specialized sites within follicles of the lymph node (LN) where B cells proliferate and undergo somatic hypermutation. Antigen availability within GCs is important, as B cells must acquire and present antigen to follicular helper T cells to drive this process. However, recombinant protein immunogens such as soluble HIV envelope (Env) trimers do not efficiently accumulate in follicles following traditional immunization. Here we demonstrate two strategies to concentrate HIV Env immunogens in follicles, via the formation of immune complexes (ICs) or by employing self-assembling protein nanoparticles for multivalent display of Env antigens. Using rhesus macaques, we show that within a few days following immunization, free trimers were present in a diffuse pattern in draining LNs, while trimer ICs and Env nanoparticles accumulated in B cell follicles. Whole LN imaging strikingly revealed that ICs and trimer nanoparticles concentrated in as many as 500 follicles in a single lymph node within 2 days after immunization. Imaging of LNs collected 7 days post-immunization showed that Env nanoparticles persisted on follicular dendritic cells in the light zone of nascent germinal centers. These findings suggest that the form of antigen administered in vaccination can dramatically impact localization in lymphoid tissues and provides a new rationale for the enhanced immune responses observed following immunization with immune complexes or nanoparticles.

immunology↗

bioRxiv2018

Slow delivery immunization enhances HIV neutralizing antibody and germinal center responses via modulation of immunodominance

The observation that humans can produce broadly neutralizing antibodies (bnAbs) against HIV-1 has generated enthusiasm about the potential for a bnAb vaccine against HIV-1. Conventional immunization strategies will likely be insufficient for the development of a bnAb HIV vaccine and vaccines to other difficult pathogens, due to the significant immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. Using longitudinal lymph node fine needle aspirates, we found that two independent methods of slow delivery immunization of rhesus macaques (RM) resulted in larger GCs, more robust and sustained GC Tfh cell responses, and GC B cells with improved Env-binding, which correlated with the development of ~20 to 30-fold higher titers of tier 2 HIV-1 nAbs. Using a new RM genomic immunoglobulin loci reference sequence, we identified differential IgV gene usage between slow delivery immunized and conventional bolus immunized animals. The most immunodominant IgV gene used by conventionally immunized animals was associated with many GC B cell lineages. Ab mapping of those GC B cell specificities demonstrated targeting of an immunodominant non-neutralizing trimer base epitope, while that response was muted in slow delivery immunized animals. Thus, alternative immunization strategies appear to enhance nAb development by altering GCs and modulating immunodominance of non-neutralizing epitopes.

immunology↗