Biology subjects

McIntyre, J.

Publications and source records attributed to McIntyre, J..

4 recordsLinked to original sources

bioRxiv2021

Genomic landscape of drug response reveals novel mediators of anthelmintic resistance

Understanding the genetic basis of anthelmintic drug resistance in parasitic nematodes is key to improving the efficacy and sustainability of parasite control. Here, we use a genetic cross in a natural host-parasite system to simultaneously map resistance loci for the three major classes of anthelmintics. This approach identifies novel alleles for resistance to benzimidazoles and levamisole and implicates the transcription factor, cky-1, in ivermectin resistance. This gene is within a locus under selection in ivermectin resistant populations worldwide; functional validation using knockout experiments supports a role for cky-1 overexpression in ivermectin resistance. Our work demonstrates the feasibility of high-resolution forward genetics in a parasitic nematode, and identifies variants for the development of molecular diagnostics to combat drug resistance in the field. One-Sentence SummaryGenetic mapping of known and novel anthelmintic resistance-associated alleles in a multi-drug resistant parasitic nematode

genomics↗

bioRxiv2021

Transcriptomic analyses implicate neuronal plasticity and chloride homeostasis in ivermectin resistance and recovery in a parasitic nematode

The antiparasitic drug ivermectin plays an essential role in human and animal health globally. However, ivermectin resistance is widespread in veterinary helminths and there are growing concerns of sub-optimal responses to treatment in related helminths of humans. Despite decades of research, the genetic mechanisms underlying ivermectin resistance are poorly understood in parasitic helminths. This reflects significant uncertainty regarding the mode of action of ivermectin in parasitic helminths, and the genetic complexity of these organisms; parasitic helminths have large, rapidly evolving genomes and differences in evolutionary history and genetic background can confound comparisons between resistant and susceptible populations. We undertook a controlled genetic cross of a multi-drug resistant and a susceptible reference isolate of Haemonchus contortus, an economically important gastrointestinal nematode of sheep, and ivermectin-selected the F2 population for comparison with an untreated F2 control. RNA-seq analyses of male and female adults of all populations identified high transcriptomic differentiation between parental isolates, which was significantly reduced in the F2, allowing differences associated specifically with ivermectin resistance to be identified. In all resistant populations, there was constitutive upregulation of a single gene, HCON_00155390:cky-1, a putative pharyngeal-expressed transcription factor, in a narrow locus on chromosome V previously shown to be under ivermectin selection. In addition, we detected sex-specific differences in gene expression between resistant and susceptible populations, including constitutive upregulation of a P-glycoprotein, HCON_00162780:pgp-11, in resistant males only. After ivermectin selection, we identified differential expression of genes with roles in neuronal function and chloride homeostasis, which is consistent with an adaptive response to ivermectin-induced hyperpolarisation of neuromuscular cells. Overall, we show the utility of a genetic cross to identify differences in gene expression that are specific to ivermectin selection and provide a framework to better understand ivermectin resistance and recovery in parasitic helminths. Author SummaryParasitic helminths (worms) infect people and animals throughout the world and are largely controlled with mass administration of anthelmintic drugs. There are a very limited number of anthelmintics available and parasitic helminths can rapidly develop resistance to these drugs. Ivermectin is a widely used anthelmintic in both humans and animals, but resistance is now widespread in the veterinary field. We crossed ivermectin resistant and ivermectin susceptible parasitic helminths and treated them with ivermectin or left them as untreated controls. This provided resistant and susceptible populations with a similar genetic background with which to study differences in gene expression associated with ivermectin resistance. We identified upregulation of a gene with no previous association with drug resistance (HCON_00155390:cky-1) in male and female worms in all resistant populations. This gene is thought to be expressed in the helminth pharynx (mouthpart) and, in mammals, plays a role in controlling nerve function and protecting nerves from damage. This is consistent with the known effects of ivermectin in inhibiting helminth feeding through pharyngeal paralysis and implicates a novel mechanism that allows resistant worms to survive treatment.

genomics↗

bioRxiv2021

EEG-Based Focus Estimation Using Neurable's Enten Headphones and Analytics Platform

We introduce Neurables research on focus using our recently developed Enten EEG headphones. First we quantify Entens performance on standard EEG protocols, including eyes-closed alpha rhythms, auditory evoked response and the P300 event-related potential paradigm. We show that Entens performance is on-par with established industry-standard hardware. We then introduce a series of experimental tasks designed to mimic how focus might be maintained or disrupted in a real-world office setting. We show that (A) these tasks induce behavioral changes that reflect underlying changes in focus levels and (B) our proprietary algorithm detects these changes across a large number of sessions without needing to adjust the model per participant or recording session. Through manipulation of our experimental protocol, we show that our algorithm is not dependent on gross EMG artifacts and it is driven by changes in EEG. Finally, we evaluated the models performance on the same subject across several days, and show that performance remained consistent over time. Our model correctly captured 80% {+/-} 4.1% of distractions present in our experiments with statistical significance. This indicates that our model generalizes across subjects, time points, and conditions. Our findings are based on EEG data collected from 132 participants across 337 sessions and 45 different experiments.

neuroscience↗

bioRxiv2020

Does gravity shape internal representations of space for human 3D perception?

Human 3D perception of visual objects is flawed by distortions, which are influenced by non-visual factors, such as gravitational vestibular signals. Whether gravity acts specifically on the visual system or at a higher, modality-independent, level of information processing remains unknown. To test these modality-specific vs modality-independent hypotheses, we performed experiments comparing visual versus haptic 3D shape perception in normo-gravity and microgravity. The results obtained for upright and supine posture in 1g show that visual and haptic perceptual anisotropies are systematically in opposing ego-centered, but not gravity-centered, directions suggesting they share a common origin. On the other hand, microgravity significantly modulates both visual and haptic perceptual distortion in the same direction. Overall, our results show a clear link between the visual and haptic perceptual distortions and demonstrate a role of gravity-related signals on a modality-independent internal representation of 3D space used to interpret incoming sensory inputs.

neuroscience↗