Biology subjects

O'Connor, N.

Publications and source records attributed to O'Connor, N..

4 recordsLinked to original sources

bioRxiv2026

Context-dependent peptide recognition shapes tyrosine kinase substrate specificity beyond consensus motifs

Protein tyrosine kinases (PTKs) regulate cellular biochemistry by phosphorylating tyrosine residues that alter protein function; their substrate preferences define the topology of signaling cascades. Previous studies of PTKs have mapped their average preferences for amino acids surrounding phosphorylation sites, but their sensitivity to sequence variation remains poorly understood. Here, we used microbial biosensors for PTK activity to examine the influence of local sequence context on substrate specificity. Across five well-studied PTKs, we identified amino acid substitutions within consensus substrates that could confer sensitivity to substrate length or enhance selectivity for one PTK over others. Using a secondary decoy screen, we found sequence-diverse substrates with unexpectedly orthogonal PTK compatibilities. Our findings show how context-specific sequence features alter PTK substrate specificity far beyond what might be expected from classical consensus models and establish an experimental framework for defining the limits of substrate overlap between closely related kinases.

biochemistry↗

bioRxiv2024

The impact of sex differences on perceived pain intensity in pain protocol standardization

BackgroundSex differences have been widely demonstrated in both acute and chronic pain. Sex differences may have wider impact on research design and analysis than already established. This study addresses an important methodological aspect with regards to how sex differences could influence the design of standardized experimental pain protocols used to characterize an individuals pain response. MethodsThis study addresses sex differences of perceived pain at tonic heat pain threshold (HPT). Participants used a computerized visual analogue scale (CoVAS) to continually rated subjective pain intensity during tonic HPT. Metrics (Mean, Standard Deviation, Maximum) were extracted from the CoVAS to characterize perceived pain. ResultsFemale participants rated pain intensity at HPT significantly lower than male participants across all extracted metrics used to characterize the coVAS rating. The effect of sex on the mean and standard deviation of pain intensity ratings at HPT was medium, while the effect size of sex on the maximum pain intensity rating at HPT was large. ConclusionThe significant sex differences in perceived pain intensity at HPT indicates that methods of standardization to a specific pain intensity merit sex-specific consideration. Additionally, these observed sex differences underscore the necessity for sex specific design across both pre-clinical and clinical studies of pain.

neuroscience↗

bioRxiv2024

Differential effects of conventional transcranial direct current stimulation (tDCS) and high-definition transcranial direct current stimulation (HD-tDCS) of the cerebellum on offset analgesia

BackgroundOffset analgesia (OA) describes the large decrease in perceived pain in response to a minor decrease in applied painful thermal stimulus. Here non-invasive brain stimulation (NIBS) is used to modulate the cerebellum, since the cerebellum is known to signal sensory prediction errors and is implicated in pain processing. MethodsAn OA protocol individualized to heat pain threshold (HPT) was applied via TSA-II (Medoc, Israel). NIBS interventions were applied prior to OA. Cathodal cerebellar transcranial direct current stimulation (tDCS) and high-definition (4X1) transcranial direct current stimulation (HD-tDCS) were applied to 46 healthy participants within a sham controlled repeated measures design to examine whether diffuse or focal stimulation differentially modulates OA. ResultsOA induced hypoalgesia was robust, with 90% of responses showing a drop in perceived pain ({delta}VAS) > 10 following the 1{degrees}C fall in temperature. This OA response was augmented following a protocol with sham and focal cathodal cerebellar stimulation on four OA parameters (OA latency, VAS minimum, VAS mean and VAS 2nd max) relative to pre-stimulation. This effect was differential to the protocol with sham and conventional tDCS where two OA metrics altered (OA duration, VAS 2nd max). ConclusionOA enhancement via cathodal cerebellar NIBS may involve both a placebo effect and sustaining a noxious sensory prediction error. Understanding how the cerebellum is involved in OA could enhance therapies for pain patients.

neuroscience↗

bioRxiv2018

Automatic navigation system for the mouse brain

Identification and delineation of brain regions in histologic mouse brain sections is especially pivotal for many neurogenomics, transcriptomics, proteomics and connectomics studies, yet this process is prone to observer error and bias. Here we present a novel brain navigation system, named NeuroInfo, whose general principle is similar to that of a global positioning system (GPS) in a car. NeuroInfo automatically navigates an investigator through the complex microscopic anatomy of histologic sections of mouse brains (thereafter: \"experimental mouse brain sections\"). This is achieved by automatically registering a digital image of an experimental mouse brain section with a three-dimensional (3D) digital mouse brain atlas that is essentially based on the third version of the Allen Mouse Brain Common Coordinate Framework (CCF v3), retrieving graphical region delineations and annotations from the 3D digital mouse brain atlas, and superimposing this information onto the digital image of the experimental mouse brain section on a computer screen. By doing so, NeuroInfo helps in solving the long-standing problem faced by researchers investigating experimental mouse brain sections under a light microscope--that of correctly identifying the distinct brain regions contained within the experimental mouse brain sections. Specifically, NeuroInfo provides an intuitive, readily-available computer microscopy tool to enhance researchers ability to correctly identify specific brain regions in experimental mouse brain sections. Extensive validation studies of NeuroInfo demonstrated that this novel technology performs remarkably well in accurately delineating regions that are large and/or located in the dorsal parts of mouse brains, independent on whether the sections were imaged with fluorescence or brightfield microscopy. This novel navigation system provides a highly efficient way for registering a digital image of an experimental mouse brain section with the 3D digital mouse brain atlas in a minute and accurate delineation of the image in real-time.

neuroscience↗