Biology subjects

Phillips, E.

Publications and source records attributed to Phillips, E..

8 recordsLinked to original sources

bioRxiv2023

Perinuclear damage from nuclear envelope deterioration elicits stress responses that contribute to LMNA cardiomyopathy

Mutations in the LMNA gene encoding nuclear lamins A/C cause a diverse array of tissue-selective diseases, with the heart being the most commonly affected organ. Despite progress in understanding the molecular perturbations emanating from LMNA mutations, an integrative understanding of the pathogenesis leading to cardiac dysfunction remains elusive. Using a novel cell-type specific Lmna deletion mouse model capable of translatome profiling, we found that cardiomyocyte-specific Lmna deletion in adult mice led to rapid cardiomyopathy with pathological remodeling. Prior to the onset of cardiac dysfunction, lamin A/C-depleted cardiomyocytes displayed nuclear envelope deterioration, golgi dilation/fragmentation, and CREB3-mediated golgi stress activation. Translatome profiling identified upregulation of Med25, a transcriptional co-factor that can selectively dampen UPR axes. Autophagy is disrupted in the hearts of these mice, which can be recapitulated by disrupting the golgi or inducing nuclear damage by increased matrix stiffness. Systemic administration of pharmacological modulators of autophagy or ER stress significantly improved the cardiac function. These studies support a hypothesis wherein stress responses emanating from the perinuclear space contribute to the development of LMNA cardiomyopathy. TeaserInterplay of stress responses underlying the development of LMNA cardiomyopathy

cell biology↗

bioRxiv2023

Targets and cross-reactivity of human T cell recognition of Common Cold Coronaviruses

The Coronavirus (CoV) family includes a variety of viruses able to infect humans. Endemic CoVs that can cause common cold belong to the alphaCoV and betaCoV genera, with the betaCoV genus also containing subgenera with zoonotic and pandemic concern, including sarbecoCoV (SARS-CoV and SARS-CoV-2) and merbecoCoV (MERS-CoV). It is therefore warranted to explore pan-CoV vaccine concepts, to provide adaptive immune protection against new potential CoV outbreaks, particularly in the context of betaCoV sub lineages. To explore the feasibility of eliciting CD4+ T cell responses widely cross-recognizing different CoVs, we utilized samples collected pre-pandemic to systematically analyze T cell reactivity against representative alpha (NL63) and beta (OC43) common cold CoVs (CCC). Similar to previous findings on SARS-CoV-2, the S, N, M, and nsp3 antigens were immunodominant for both viruses while nsp2 and nsp12 were immunodominant for NL63 and OC43, respectively. We next performed a comprehensive T cell epitope screen, identifying 78 OC43 and 87 NL63-specific epitopes. For a selected subset of 18 epitopes, we experimentally assessed the T cell capability to cross-recognize sequences from representative viruses belonging to alphaCoV, sarbecoCoV, and beta-non-sarbecoCoV groups. We found general conservation within the alpha and beta groups, with cross-reactivity experimentally detected in 89% of the instances associated with sequence conservation of >67%. However, despite sequence conservation, limited cross-reactivity was observed in the case of sarbecoCoV (50% of instances), indicating that previous CoV exposure to viruses phylogenetically closer to this subgenera is a contributing factor in determining cross-reactivity. Overall, these results provided critical insights in the development of future pan-CoV vaccines.

immunology↗

bioRxiv2022

Mucosal gene expression in response to SARS-CoV-2 is associated with early viral load.

Little is known about the relationships between symptomatic early-time SARS-CoV-2 viral load and upper airway mucosal gene expression and immune response. To examine the association of symptomatic SARS-CoV-2 early viral load with upper airway mucosal gene expression, we profiled the host mucosal transcriptome from nasopharyngeal swab samples from 68 adults with symptomatic, mild-to-moderate COVID-19. We measured SARS-CoV-2 viral load using qRT-PCR. We then examined the association of SARS-CoV-2 viral load with upper airway mucosal immune response. We detected SARS-CoV-2 in all samples and recovered >80% of the genome from 85% of the samples from symptomatic COVID-19 adults. The respiratory virome was dominated by SARS-CoV-2, with limited co-detection of common respiratory viruses i.e., only the human Rhinovirus (HRV) being identified in 6% of the samples. We observed a significant positive correlation between SARS-CoV-2 viral load and interferon signaling (OAS2, OAS3, IFIT1, UPS18, ISG15, ISG20, IFITM1, and OASL), chemokine signaling (CXCL10 and CXCL11), and adaptive immune system (IFITM1, CD300E, and SIGLEC1) genes in symptomatic, mild-to-moderate COVID-19 adults, when adjusted for age, sex and race. Interestingly, the expression levels of most of these genes plateaued at a CT value of ~25. Overall, our data shows that early nasal mucosal immune response to SARS-CoV-2 infection is viral load dependent, which potentially could modify COVID-19 outcomes. AUTHOR SUMMARYSeveral prior studies have shown that SARS-CoV-2 viral load can predict the likelihood of disease spread and severity. A higher detectable SARS-CoV-2 plasma viral load was associated with worse respiratory disease severity. However, the relationship between SARS-CoV-2 viral load and airway mucosal gene expression and immune response remains elusive. We profiled the nasal mucosal transcriptome from nasal samples collected from adults infected with SARS-CoV-2 during Spring 2020 with mild-to-moderate symptoms using a comprehensive metatranscriptomics method. We observed a positive correlation between SARS-CoV-2 viral load with interferon signaling, chemokine signaling, and adaptive immune system in adults with COVID-19. Our data suggest that early nasal mucosal immune response to SARS-CoV-2 infection was viral load-dependent and may modify COVID-19 outcomes.

genomics↗

bioRxiv2022

Gaze onsets during naturalistic infant-caregiver interaction associate with 'sender' but not 'receiver' neural responses, and do not lead to changes in inter-brain synchrony.

Temporal coordination during infant-caregiver social interaction is thought to be crucial for supporting early language acquisition and cognitive development. Despite a growing prevalence of theories suggesting that increased inter-brain synchrony associates with many key aspects of social interactions such as mutual gaze, little is known about how this arises during development. Here, we investigated the role of mutual gaze onsets as a potential driver of inter-brain synchrony. We extracted dual EEG activity around naturally occurring gaze onsets during infant-caregiver social interactions in N=55 dyads (mean age 12 months). We differentiated between two types of gaze onset, depending on each partners role. Sender gaze onsets were defined at a time when either the adult or the infant made a gaze shift towards their partner at a time when their partner was either already looking at them (mutual) or not looking at them (non-mutual). Receiver gaze onsets were defined at a time when their partner made a gaze shift towards them at a time when either the adult or the infant was already looking at their partner (mutual) or not (non-mutual). Contrary to our hypothesis we found that, during a naturalistic interaction, both mutual and non-mutual gaze onsets were associated with changes in the sender, but not the receivers brain activity and were not associated with increases in inter-brain synchrony above baseline. Further, we found that mutual, compared to non-mutual gaze onsets were not associated with increased inter brain synchrony. Overall, our results suggest that the effects of mutual gaze are strongest at the intra-brain level, in the sender but not the receiver of the mutual gaze.

neuroscience↗

bioRxiv2021

SARS-CoV-2 vaccination induces immunological memory able to cross-recognize variants from Alpha to Omicron

We address whether T cell responses induced by different vaccine platforms (mRNA-1273, BNT162b2, Ad26.COV2.S, NVX-CoV2373) cross-recognize SARS-CoV-2 variants. Preservation of at least 83% and 85% for CD4+ and CD8+ T cell responses was found, respectively, regardless of vaccine platform or variants analyzed. By contrast, highly significant decreases were observed for memory B cell and neutralizing antibody recognition of variants. Bioinformatic analyses showed full conservation of 91% and 94% of class II and class I spike epitopes. For Omicron, 72% of class II and 86% of class I epitopes were fully conserved, and 84% and 85% of CD4+ and CD8+ T cell responses were preserved. In-depth epitope repertoire analysis showed a median of 11 and 10 spike epitopes recognized by CD4+ and CD8+ T cells from vaccinees. Functional preservation of the majority of the T cell responses may play an important role as a second-level defense against diverse variants.

immunology↗

bioRxiv2021

Using dual EEG to analyse event-locked changes in child-adult neural connectivity

Current approaches typically measure the connectivity between interacting physiological systems as a time-invariant property. This approach obscures crucial information about how connectivity between interacting systems is established and maintained. Here, we describe methods, and present computational algorithms, that will allow researchers to address this deficit. We focus on how two different approaches to measuring connectivity, namely concurrent (e.g., power correlations, phase locking) and sequential (e.g., Granger causality), can be applied to three aspects of the brain signal, namely amplitude, power, and phase. We guide the reader through worked examples using mainly simulated data on how to leverage these methods to measure changes in interbrain connectivity between adults and children/infants relative to events identified within continuous EEG data during a free-flowing naturalistic interaction. For each, we aim to provide a detailed explanation of the interpretation of the analysis and how they can be usefully used when studying early social interactions.

neuroscience↗

bioRxiv2021

Automatic classification of ICA components from infant EEG using MARA

Automated systems for identifying and removing non-neural ICA components are growing in popularity among adult EEG researchers. Infant EEG data differs in many ways from adult EEG data, but there exists almost no specific system for automated classification of source components from paediatric populations. Here, we adapt one of the most popular systems for adult ICA component classification for use with infant EEG data. Our adapted classifier significantly outperformed the original adult classifier on samples of naturalistic free play EEG data recorded from 10 to 12-month-old infants, achieving agreement rates with the manual classification of over 75% across two validation studies (n=44, n=25). Additionally, we examined both classifiers ability to remove stereotyped ocular artifact from a basic visual processing ERP dataset, compared to manual ICA data cleaning. Here the new classifier performed on level with expert manual cleaning and was again significantly better than the adult classifier at removing artifact whilst retaining a greater amount of genuine neural signal, operationalised through comparing ERP activations in time and space. Our new system (iMARA) offers developmental EEG researchers a flexible tool for automatic identification and removal of artifactual ICA components.

neuroscience↗

bioRxiv2020

Design and Performance Evaluation of a Wearable Passive Cable-driven Shoulder Exoskeleton

The mechanical assistance provided by exoskeletons could potentially replace, assist, or rehabilitate upper extremity function in patients with mild to moderate shoulder disability to perform activities of daily living. While many exoskeletons are "active" (e.g. motorized), mechanically passive exoskeletons may be a more practical and affordable solution to meet a growing clinical need for continuous, home-based movement assistance. In the current study, we designed, fabricated, and evaluated the performance of a wearable, passive, cable-driven shoulder exoskeleton (WPCSE) prototype. An innovative feature of the WPCSE is a modular spring-cam-wheel system that can be custom designed to compensate for any proportion of the shoulder elevation moment due to gravity over a large range of shoulder motion. The force produced by the spring-cam-wheel system is transmitted over the superior aspect of the shoulder to an arm cuff through a Bowden cable. The results from mechanical evaluation revealed that the modular spring-cam-wheel system could successfully produce an assistive positive shoulder elevation moment that matched the desired, theoretical moment. However, when measured from the physical WPCSE prototype, the moment was lower (up to 30%) during positive shoulder elevation and higher (up to 120%) during negative shoulder elevation due primarily to friction. Even so, our biomechanical evaluation showed that the WPCSE prototype reduced the root mean square (up to 35%) and peak (up to 33%) muscular activity, as measured by electromyography, of several muscles crossing the shoulder during shoulder elevation and horizontal adduction/abduction movements. These preliminary results suggest that our WPCSE may be suitable for providing movement assistance to people with shoulder disability.

bioengineering↗