Biology subjects

Barnett, M.

Publications and source records attributed to Barnett, M..

8 recordsLinked to original sources

bioRxiv2023

Structure of a benzosulfonamide based inhibitor 11l bound to a disulfide stabilised HIV-1 capsid hexamer

The Human Immunodeficiency Virus Type 1 (HIV-1) continues to be a major global health issue, with infection leading to Acquired Immunodeficiency Syndrome (AIDS). Despite advances in antiviral therapy, the need for new and more effective treatments remains critical. In this study, we determined the structure of the disulfide stabilised HIV-1 capsid protein hexamer in complex with the novel antiviral capsid inhibitor compound 11l. The structure revealed the presence of six 11l molecules bound to the capsid hexamer in a conserved site shared by nuclear import factors, and other capsid inhibitor compounds such as PF74 and GS-6207. The 11l compound exhibits disorder in the benzo-sulfonamide groups and disruption in the loop between helix 8 and 9 for the capsid C-terminal domain, an important 2-fold symmetry axis for hexamer formation. Our findings provide insights into the mechanism of action of 11l as a capsid inhibitor and antiviral. These results contribute to the ongoing efforts to develop more effective antiviral treatments for the global burden of HIV and AIDS. SynopsisInsight into the mechanism of action for a novel HIV-1 capsid inhibitor antivirals are elucidated by structure of HIV-1 capsid hexamer bound to the novel inhibitor compound 11l.

biochemistry↗

bioRxiv2022

The mutational landscape of single neurons and oligodendrocytes reveals evidence of inflammation-associated DNA damage in multiple sclerosis

Neuroinflammation has been linked to DNA damage in multiple sclerosis (MS), but its impact on neural cell genomes at nucleotide resolution is unknown. To address this question, we performed single nucleus whole genome sequencing to determine the landscape of somatic mutation in 172 neurons and oligodendrocytes (OLs) extracted from post-mortem brain tissue from 5 MS cases and three controls. We identified two cases with a significant excess of somatic single nucleotide variants (sSNV) in neurons and OLs from MS inflammatory demyelinated lesions. For a case with primary progressive MS, this translated to a 68% increase in sSNV frequency and 32-year equivalent increase in biological age of lesion-resident cells. Mutational signature analysis conducted on all cells revealed that defective DNA repair and transcription-associated DNA damage are important mutagenic mechanism in both neurons and OLs in MS. Our findings provide the first evidence that inflammation in the brains of people with MS is associated with DNA damage, which may have implications for other neurodegenerative diseases and future drug development.

genomics↗

bioRxiv2021

FOD-Net: A Deep Learning Method for Fiber Orientation Distribution Angular Super Resolution

Mapping the human connectome using fiber-tracking permits the study of brain connectivity and yields new insights into neuroscience. However, reliable connectome reconstruction using diffusion magnetic resonance imaging (dMRI) data acquired by widely available clinical protocols remains challenging, thus limiting the connectome / tractography clinical applications. Here we develop fiber orientation distribution (FOD) network (FOD-Net), a deep-learning-based framework for FOD angular super-resolution. Our method enhances the angular resolution of FOD images computed from common clinical-quality dMRI data, to obtain FODs with quality comparable to those produced from advanced research scanners. Super-resolved FOD images enable superior tractography and structural connectome reconstruction from clinical protocols. The method was trained and tested with high-quality data from the Human Connectome Project (HCP) and further validated with a local clinical 3.0T scanner. Using this method, we improve the angular resolution of FOD images acquired with typical single-shell low-angular-resolution dMRI data (e.g., 32 directions, b = 1000 s/mm2) to approximate the quality of FODs derived from time-consuming, multi-shell high-angular-resolution dMRI research protocols. We also demonstrate tractography improvement, removing spurious connections and bridging missing connections. We further demonstrate that connectomes reconstructed by super-resolved FODs achieve comparable results to those obtained with more advanced dMRI acquisition protocols, on both HCP and clinical 3.0T data. Advances in deep-learning approaches used in FOD-Net facilitate the generation of high quality tractography / connectome analysis from existing clinical MRI environments. Our code is freely available at https://github.com/ruizengalways/FOD-Net.

bioengineering↗

bioRxiv2019

Immunotherapy prevents long-term disability in relapsing multiple sclerosis over 15 years

ObjectiveWhether immunotherapy improves long-term disability in multiple sclerosis has not been satisfactorily demonstrated. This study examined the effect of immunotherapy on long-term disability outcomes in relapsing-remitting multiple sclerosis.\n\nMethodsWe studied patients from MSBase followed for [≥]1 year, with [≥]3 visits, [≥]1 visit per year and exposed to a multiple sclerosis therapy, and a subset of patients with [≥]15-year follow-up. Marginal structural models were used to compare the hazard of 12-month confirmed increase and decrease in disability, EDSS step 6 and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously re-adjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability and MRI activity.\n\nResults14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval 0.43-0.82, p=0.0016), worsening of disability (0.56, 0.38-0.82, p=0.0026) and progress to EDSS step 6 (0.33, 0.19-0.59, p=0.00019). Among 1085 patients with [≥]15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50-0.70, p=10-9) and worsening of disability (0.81, 0.67-0.99, p=0.043).\n\nConclusionsContinued treatment with multiple sclerosis immunotherapies reduces disability accrual (by 19-44%), the risk of need of a walking aid by 67% and the frequency of relapses (by 40-41%) over 15 years. A proof of long-term effect of immunomodulation on disability outcomes is the key to establishing its disease modifying properties.

neuroscience↗

bioRxiv2018

Novel childhood experience suggests eccentricity drives organization of human visual cortex

The functional organization of human high-level visual cortex, such as face and place-selective regions, is strikingly consistent across individuals. A fundamental, unanswered question in neuroscience is what dimensions of visual information constrain the development and topography of this shared brain organization? To answer this question, we scanned with fMRI a unique group of adults who, as children, engaged in extensive experience with a novel stimulus-Pokemon-which are dissimilar from other ecological categories such as faces and places along critical dimensions (foveal bias, rectilinearity, size, animacy) from. We find that experienced adults not only demonstrate distinct and consistent distributed cortical responses to Pokemon, but their activations suggest that it is the experienced retinal eccentricity during childhood that predicts the locus of distributed responses to Pokemon in adulthood. These data advance our understanding about how childhood experience and functional constraints shape the functional organization of the human brain.

neuroscience↗

bioRxiv2018

Apparent thinning of visual cortex during childhood is associated with myelination, not pruning

Microstructural mechanisms underlying apparent cortical thinning during childhood development are unknown. Using functional, quantitative, and diffusion magnetic resonance imaging in children and adults, we tested if tissue growth (lower T1 relaxation time and mean diffusivity (MD)) or pruning (higher T1 and MD) underlies cortical thinning in ventral temporal cortex (VTC). After age 5, T1 and MD decreased in mid and deep cortex of functionally-defined regions in lateral VTC, and in their adjacent white matter. T1 and MD decreases were (i) consistent with tissue growth related to myelin proliferation, which we verified with adult postmortem histology and (ii) correlated with apparent cortical thinning. Thus, contrary to prevailing theories, cortical tissue does not thin during childhood, it becomes more myelinated, shifting the gray-white matter boundary deeper into cortex. As tissue growth is prominent in regions with protracted functional development, our data suggest an intriguing hypothesis that functional development and myelination are interlinked.

neuroscience↗

bioRxiv2018

Learning to read increases the informativeness of distributed ventral temporal responses

Becoming a proficient reader requires substantial learning over many years. However, it is unknown how learning to read affects development of distributed visual representations across human ventral temporal cortex (VTC). Using fMRI and a data-driven, computational approach, we quantified the development of distributed VTC responses to characters (pseudowords and numbers) vs. other domains in children, preteens, and adults. Results reveal anatomical- and hemisphere-specific development. With development, distributed responses to words and characters became more distinctive and informative in lateral but not medial VTC, and in the left but not right hemisphere. While development of voxels with both positive (that is, word-selective) and negative preference to words affected distributed information, only development of word-selective voxels predicted reading ability. These data show that developmental increases in informativeness of distributed left lateral VTC responses enable proficient reading and have important implications for both developmental theories and for elucidating neural mechanisms of reading disabilities.

neuroscience↗

bioRxiv2017

Development differentially sculpts receptive fields across human visual cortex

Receptive fields (RFs) processing information in restricted parts of the visual field are a key property of neurons in the visual system. However, how RFs develop in humans is unknown. Using fMRI and population receptive field (pRF) modeling in children and adults, we determined where and how pRFs develop across the ventral visual stream. We find that pRF properties in visual field maps, V1 through VO1, are adult-like by age 5. However, pRF properties in face- and word-selective regions develop into adulthood, increasing the foveal representation and the visual field coverage for faces in the right hemisphere and words in the left hemisphere. Eye-tracking indicates that pRF changes are related to changing fixation patterns on words and faces across development. These findings suggest a link between viewing behavior of faces and words and the differential development of pRFs across visual cortex, potentially due to competition on foveal coverage.

neuroscience↗