Biology subjects

Donaldson, R.

Publications and source records attributed to Donaldson, R..

4 recordsLinked to original sources

bioRxiv2022

Differential response of patient-derived primary glioblastoma cells to metabolic and adhesion inhibitors

PurposeThis study aims to investigate Glioblastoma (GBM) cellular response to adhesion and metabolic inhibitors in the context of cells migration and cell-matrix adhesion properties. GBM is the most common incurable brain tumour. Decades of work into GBM chemical and molecular classification have identified mechanisms of drug resistance. Inhibitors targeting cancer cell migration and proliferation rarely take into consideration the heterogeneous migration property amongst cells, which may impact patients response to treatment. MethodsTissue samples were obtained from spatially distinct locations with different 5-aminolevulinic acid (5-ALA) fluorescent intensities, strong strongly fluorescent tumour cores, a weak fluorescent tumour rim, and nonfluorescent tumour margins. Samples were previously shown to be associated with different motility and adhesion properties. We tested tumour cells response to adhesion and metabolic inhibitors using metabolic assays. Cell survival was also monitored using time-lapse microscopy, while cultured on low-modulus polydimethylsiloxane representative of the stiffness of brain tissue. ResultsMetabolic viability assays, MTT and Cell Titer, showed substantial heterogeneity in drug potency. Highly fluorescent tumour core cells were significantly more resistant to an F0F1 ATP synthase inhibitor (Gboxin), and a FAK inhibitor (GSK2256098), and cell proliferation ceased post-treatment in vitro. Cells derived from non-fluorescent tumour margins exhibited higher potency for the ATP synthase inhibitor (Gboxin). However, cell proliferation persisted post-treatment. ConclusionOur study suggests that the adhesive and migration properties of cells account for the sensitivity to therapeutics in different regions of the tumour in individual patients and between patients with GBM.

neuroscience↗

bioRxiv2020

High Throughput Computational Mouse Genetic Analysis

BackgroundGenetic factors affecting multiple biomedical traits in mice have been identified when GWAS data that measured responses in panels of inbred mouse strains was analyzed using haplotype-based computational genetic mapping (HBCGM). Although this method was previously used to analyze one dataset at a time; but now, a vast amount of mouse phenotypic data is now publicly available, which could lead to many more genetic discoveries. ResultsHBCGM and a whole genome SNP map covering 53 inbred strains was used to analyze 8462 publicly available datasets of biomedical responses (1.52M individual datapoints) measured in panels of inbred mouse strains. As proof of concept, causative genetic factors affecting susceptibility for eye, metabolic and infectious diseases were identified when structured automated methods were used to analyze the output. One analysis identified a novel genetic effector mechanism; allelic differences within the mitochondrial targeting sequence affected the subcellular localization of a protein. We also found allelic differences within the mitochondrial targeting sequences of many murine and human proteins, and these could affect a wide range of biomedical phenotypes. ImplicationsThese initial results indicate that genetic factors affecting biomedical responses could be identified through analysis of very large datasets, and they provide an early indication of how this type of augmented intelligence can facilitate genetic discovery.

bioinformatics↗

bioRxiv2020

Skill acquisition and gaze behavior during laparoscopic surgical simulation

BackgroundExperts consistently exhibit more efficient gaze behaviors than non-experts during motor tasks. In surgery, experts have been shown to gaze more at surgical targets than surgical tools during simple simulations and when watching surgical recordings, suggesting a proactive control strategy with greater use of feedforward visual sampling. To investigate such expert gaze behaviors in a more dynamic and complex laparoscopic surgery simulation, the current study measured and compared gaze patterns between surgeons and novices who practiced extensively with laparoscopic simulation. MethodsThree surgeons were assessed in a testing visit and five novices were trained and assessed (at pre-, mid-, and post-training points) in a 5-visit protocol on the Fundamentals of Laparoscopic Surgery peg transfer task. The task was adjusted to have a fixed action sequence to allow recordings of dwell durations based on pre-defined areas of interest (AOIs). Novices individualized learning curves were analyzed using an inverse function model, and group-level differences were tested using analysis of variance on both behavioral performance and dwell duration measures. ResultsTrained novices were shown to reach more than 98% (M = 98.62%, SD = 1.06%) of their behavioral learning plateaus, leading to equivalent behavioral performance to that of surgeons. Despite this equivalence in behavioral performance, surgeons continued to show significantly shorter dwell durations at visual targets of current actions and longer dwell durations at future steps in the action sequence than trained novices (ps [≤] .03, Cohens ds > 2). ConclusionThis study demonstrates that, whereas novices can train to match surgeons on behavioral performance, their gaze pattern is still less efficient than that of surgeons, suggesting that eye-tracking metrics might be more sensitive than behavioral performance in detecting surgical expertise. Such insight can be applied to develop training protocols so non-experts can internalize experts "gaze templates" to accelerate learning. Article SummaryGaze pattern differences persist between laparoscopic surgery experts and novices who have been trained to reach over 98% of individualized behavioral learning plateaus in the Fundamentals of Laparoscopic Surgery (FLS) peg transfer task. The importance of this finding lies in motivating the decision and method of including gaze behaviors via eyetracking technology in the present surgical training programs.

neuroscience↗

bioRxiv2019

Application of long-interval paired-pulse transcranial magnetic stimulation to motion-sensitive visual cortex does not lead to changes in motion perception

The perception of visual motion is dependent on a set of occipitotemporal regions which are readily accessible to neuromodulation. Previous studies using paired-pulse Transcranial Magnetic Stimulation (ppTMS) have provided evidence of the capacity of this type of protocols to modulate cognitive processes. To test whether such cortical modulation can be observed in the visual system, particularly during motion perception, ppTMS was applied to the occipital cortex using both scalp-based and meta-analytic targeting coordinates. In this within-subject, sham-controlled study, fifteen subjects completed two sessions in two consecutive weeks. On the first visit, subject-specific resting motor threshold (RMT) was determined and participants performed an adaptive motion discrimination task to determine individual motion sensitivity. During the second visit, subjects performed the same task with three individualized difficulty levels as two TMS pulses were delivered respectively -150 and -50 ms prior to motion stimulus onset at 120% RMT, under the logic that the cumulative inhibitory effect of these two pulses would alter motion sensitivity as measured by the individually calibrated task. The ppTMS was delivered at one of two locations: 3 cm dorsal and 5 cm lateral to inion (scalp-based coordinate), or at the site of peak activation for \"motion\" according to the NeuroSynth fMRI database (meta-analytic coordinate). Sham stimulation was delivered on one-third of trials and evenly between the two targets. Analyses showed no significant active-versus-sham effects of ppTMS when stimulation was delivered to the meta-analytic (p = 0.15) or scalp-based coordinates (p = 0.17), which were separated by 29 mm on average. Additionally, there was no was significant interaction between ppTMS at either location and task difficulty level (p = 0.12 and p = 0.33, respectively). These findings fail to support the hypothesis that long-interval ppTMS recruits inhibitory processes in motion-sensitive cortex, but must be considered within the limits of the current design choices.\n\nHIGHLIGHTSO_LILong-interval paired-pulse TMS was applied to visual cortex during a motion task\nC_LIO_LIThe ppTMS was delivered according to scalp and meta-analytic coordinates, as well as sham\nC_LIO_LINo effects of active-versus-sham stimulation were observed on motion task performance\nC_LI

neuroscience↗