Biology subjects

Yau, Y.

Publications and source records attributed to Yau, Y..

6 recordsLinked to original sources

bioRxiv2024

Profiling serum immunodominance following SARS-CoV-2 primary and breakthrough infection reveals distinct variant-specific epitope usage and immune imprinting.

Over the course of the COVID-19 pandemic, variants have emerged with increased mutations and immune evasive capabilities. This has led to breakthrough infections (BTI) in vaccinated individuals, with a large proportion of the neutralizing antibody response targeting the receptor binding domain (RBD) of the SARS-CoV-2 Spike glycoprotein. Immune imprinting, where prior exposure of an antigen to the immune system can influence the response to subsequent exposures, and its role in a population with heterogenous exposure histories has important implications in future vaccine design. Here, we develop an accessible approach to map epitope immunodominance of the neutralizing antibody response in sera. By using a panel of mutant Spike in a pseudovirus neutralization assay, we observed distinct epitope usage in convalescent donors infected during wave 1, or infected with the Delta, or BA.1 variants, highlighting the antigenic diversity of the variant Spikes. Analysis of longitudinal serum samples taken spanning 3 doses of vaccine and subsequent breakthrough infection (BTI), showed the influence of immune imprinting from the ancestral-based vaccine, where reactivation of existing B cells elicited by the vaccine resulted in the enrichment of the pre-existing epitope immunodominance. However, subtle shifts in epitope usage in sera were observed following BTI by Omicron sub-lineage variants. Antigenic distance of Spike, time after last exposure, and number of vaccine boosters may play a role in the persistence of imprinting from the vaccine. This study provides insight into RBD neutralizing epitope usage in individuals with varying exposure histories and has implications for design of future SARS-CoV-2 vaccines. Author SummaryThroughout the COVID-19 pandemic, the continued emergence of new SARS-CoV-2 variants has resulted in a rise in breakthrough infections (BTIs). Infection with different variants has led to varying exposure histories in the general population. Although the neutralizing response to Spike has been thoroughly characterized, with several key epitopes identified, there is a lack of knowledge of the proportion each epitope contributes to the neutralizing response in sera and how this is affected by exposure history. Here, we use a panel of mutant Spike pseudoviruses to screen epitope usage and immunodominance in polyclonal sera. In a cohort of unvaccinated donors infected with different variants, distinct epitope usage was observed, highlighting the antigenic diversity between the variant Spikes. Furthermore, samples collected spanning multiple vaccine doses and BTI showed the influence of prior immunity from the vaccine on epitope usage. Although a large proportion of the immune response following BTI could be attributed to enrichment of pre-existing immunodominance from the vaccine, subtle shifts in epitope usage were observed with infection by more mutated variants. This work gives more detailed insight into differences in the neutralizing response of individuals with varying exposure histories that may inform next generation SARS-CoV-2 vaccines.

immunology↗

bioRxiv2022

Omicron breakthrough infections in vaccinated or previously infected hamsters

The second and third years of the SARS-CoV-2 pandemic have been marked by the repeated emergence and replacement of variants with genetic and phenotypic distance from the ancestral strains, the most recent examples being Delta and Omicron. Here we describe a hamster contact exposure challenge model to assess protection conferred by vaccination or prior infection against re-infection. We found that 2-doses of self-amplifying RNA vaccine based on the ancestral spike ameliorated weight loss following Delta infection and decreased viral loads, but had minimal effect on Omicron/BA.1 infection. Prior infection with ancestral or Alpha variant was partially protective against Omicron/BA.1 infection, whereas all animals previously infected with Delta and exposed to Omicron became infected, although shed less virus. We further tested whether prior infection with Omicron/BA.1 protected from re-infection with Delta or Omicron/BA.2. Omicron/BA.1 was protective against Omicron/BA.2, but not Delta reinfection, again showing Delta and Omicron have a very large antigenic distance. Indeed, cross-neutralisation assays with human antisera from otherwise immunonaive individuals (unvaccinated and no known prior infection), confirmed a large antigenic distance between Delta and Omicron. Prior vaccination followed by Omicron or Delta breakthrough infection led to a higher degree of cross-reactivity to all tested variants. To conclude, cohorts whose only immune experience of COVID is Omicron/BA.1 infection may be particularly vulnerable to future circulation of Delta or Delta-like derivatives. In contrast, repeated exposure to antigenically distinct spikes, via infection and or vaccination drives a more cross-reactive immune response, both in hamsters and people. One Sentence SummaryInfection with the Delta and Omicron SARS-CoV-2 variants do not provide cross-protective immunity against reinfection with one another in hamsters.

microbiology↗

bioRxiv2020

Evidence and urgency-related EEG signals during dynamic decision-making in humans

A successful class of models link decision-making to brain signals by assuming that evidence accumulates to a decision threshold. These evidence accumulation models have identified neuronal activity that appears to reflect sensory evidence and decision variables that drive behavior. More recently, an additional evidence-independent and time-variant signal, named urgency, has been hypothesized to accelerate decisions in the face of insufficient evidence. However, most decision-making paradigms tested with fMRI or EEG in humans have not been designed to disentangle evidence accumulation from urgency. Here we use a face-morphing decision-making task in combination with EEG and a hierarchical Bayesian model to identify neural signals related to sensory and decision variables, and to test the urgency-gating model. We find that an evoked potential time-locked to the decision, the centroparietal positivity, reflects the decision variable from the computational model. We further show that the unfolding of this signal throughout the decision process best reflects the product of sensory evidence and an evidence-independent urgency signal. Urgency varied across subjects, suggesting that it may represent an individual trait. Our results show that it is possible to use EEG to distinguish neural signals related to sensory evidence accumulation, decision variables, and urgency. These mechanisms expose principles of cognitive function in general and may have applications to the study of pathological decision-making as in impulse control and addictive disorders. Significance StatementPerceptual decisions are often described by a class of models that assumes sensory evidence accumulates gradually over time until a decision threshold is reached. In the present study, we demonstrate that an additional urgency signal impacts how decisions are formed. This endogenous signal encourages one to respond as time elapses. We found that neural decision signals measured by EEG reflect the product of sensory evidence and an evidence-independent urgency signal. A nuanced understanding of human decisions, and the neural mechanisms that support it, can improve decision-making in many situations and potentially ameliorate dysfunction when it has gone awry.

neuroscience↗

bioRxiv2019

Neural correlates of evidence and urgency during human perceptual decision-making in dynamically changing conditions

Current models of decision-making assume that the brain gradually accumulates evidence and drifts towards a threshold which, once crossed, results in a choice selection. These models have been especially successful in primate research, however transposing them to human fMRI paradigms has proved challenging. Here, we exploit the face-selective visual system and test whether decoded emotional facial features from multivariate fMRI signals during a dynamic perceptual decision-making task are related to the parameters of computational models of decision-making. We show that trial-by-trial variations in the pattern of neural activity in the fusiform gyrus reflect facial emotional information and modulate drift rates during deliberation. We also observed an inverse-urgency signal based in the caudate nucleus that was independent of sensory information but appeared to slow decisions, particularly when information in the task was ambiguous. Taken together, our results characterize how decision parameters from a computational model (i.e., drift rate and urgency signal) are involved in perceptual decision-making and reflected in the activity of the human brain.

neuroscience↗

bioRxiv2019

Neuroanatomical Changes in White and Grey Matter after Sleeve Gastrectomy

BackgroundMRI studies show that obese adults have reduced grey (GM) and white matter (WM) tissue density as well as altered WM integrity. It remains to be examined if bariatric surgery induces structural brain changes. The aim of this study is to characterize GM and WM density changes in a longitudinal setting, comparing pre- and post-operation and to determine whether these changes are related to inflammation and cardiometabolic markers.\n\nMethods29 severely obese participants (age: 45.9{+/-}7.8 years) scheduled to undergo sleeve gastrectomy (SG) were recruited. High-resolution T1-weighted anatomical images were acquired 1 month prior to as well as 4 and 12 months after surgery. GM and WM densities were quantified using voxel-based morphometry (VBM). Circulating lipid profile, glucose, insulin and inflammatory markers (interleukin (IL)-6, C-reactive protein (CRP) and lipopolysaccharide-binding protein (LBP) were measured at each time point. A linear mixed effect model was used to compare brain changes before and after SG, controlling for age, gender, initial BMI and diabetic status. To assess the associations between changes in adiposity, metabolism and inflammation and changes in GM or WM density, the mean GM and WM densities were extracted across all the participants using atlas, and linear mixed-effect models were used.\n\nResultsAs expected, weight, BMI, waist circumference and neck circumference significantly decreased after SG compared with baseline (p<0.001 for all). A widespread increase in WM density was observed after surgery, particularly in the cerebellum, brain stem, cerebellar peduncle, cingulum, corpus callosum and corona radiata (p<0.05, after FDR correction). Significant increases in GM density were observed 4 months after SG compared to baseline in several brain regions such as the bilateral occipital cortex, temporal cortex, precentral gyrus and cerebellum as well as right fusiform gyrus, right hippocampus and right insula. These GM and WM increases were more pronounced and widespread after 12 months and were significantly associated with post-operative weight loss and the improvement of metabolic alterations. Our linear mixed-effect models also showed strong associations between post-operative reductions in LBP, a marker of inflammation, and increased WM density. To confirm our results, we tested whether the peak of each significant region showed BMI-related differences in an independent dataset (Human Connectome Project). We matched a group of severely obese individuals with a group of lean individuals for age, gender and ethnicity. Severe obesity was associated with reduced WM density in the brain stem and cerebellar peduncle as well as reduced GM density in cerebellum, regions that significantly changed after surgery (p<0.01 for all clusters).\n\nConclusionsBariatric surgery-induced weight loss and improvement in metabolic alterations is associated with widespread increases in WM and GM densities. These post-operative changes overlapped with baseline brain differences between severely obese and normal-weight individuals, which may suggest a recovery of WM and GM alterations after bariatric surgery.

neuroscience↗

bioRxiv2017

White Matter Hyperintensities and Cognitive Decline in de Novo Parkinson’s Disease Patients

ObjectiveWhite Matter Hyperintensities (WMHs) are associated with cognitive decline in normative aging and Alzheimers disease. However, the pathogenesis of cognitive decline in Parkinsons disease (PD) is not directly related to vascular causes, and therefore the role of WMHs in PD remains unclear. If WMH has a higher impact on cognitive decline in PD, vascular pathology should be assessed and treated with a higher priority in this population. Here we investigate whether WMH leads to increased cognitive decline in PD, and if these effects relate to cortical thinning\n\nMethodsTo investigate the role of WMHs in PD, it is essential to study recently-diagnosed/non-treated patients. De novo PD patients and age-matched controls (NPD=365,NControl=174) with FLAIR/T2-weighted scans at baseline were selected from Parkinsons Progression Markers Initiative (PPMI). WMHs and cortical thickness were measured to analyse the relationship between baseline WMHs and future cognitive decline (follow-up:4.09{+/-}1.14 years) and cortical thinning (follow-up:1.05{+/-}0.10 years).\n\nResultsHigh WMH load (WMHL) at baseline in PD was associated with increased cognitive decline, significantly more than i) PDs with low WMHL and ii) controls with high WMHL. Furthermore, PD patients with higher baseline WMHL showed more cortical thinning in right frontal lobe than subjects with low WMHL. Cortical thinning of this region also predicted decline in performance on a cognitive test.\n\nInterpretationPresence of WMHs in de novo PD patients predicts greater future cognitive decline and cortical thinning than in normal aging. Recognizing WMHs as a potential predictor of cognitive deficit in PD provides an opportunity for timely interventions.

neuroscience↗