Biology subjects

Nicholson, E.

Publications and source records attributed to Nicholson, E..

9 recordsLinked to original sources

bioRxiv2026

RSV Infects the Human Nasal Epithelium via the Basolateral Route with Distinct Subgroup Infectivity and Basal Cell Tropism

Respiratory syncytial virus (RSV) causes millions of lower respiratory tract infections (LRTIs) in young children, older adults, and immunocompromised populations every year. RSV infection initiates in the upper respiratory tract and can progress to the lower airways resulting in bronchiolitis, pneumonia, and even death. RSV primarily infects epithelial cells apically, but we hypothesized that basolateral exposure of the respiratory epithelium could provide an alternative mechanism of infection that contributes to LRTI development. Using a human nose organoid-air liquid interface (HNO-ALI) model, we performed apical and basolateral inoculations with contemporaneous RSV strains (RSV/A/ON and RSV/B/BA) representing the two RSV subgroups (A and B) in both adult and infant derived HNO-ALIs. Basolateral RSV exposure resulted in delayed viral replication and apical release compared to apical infection. A statistically significant difference in basolateral infection frequency was observed between RSV/B/BA and RSV/A/ON (81.3% versus 25%). Basolateral infection selectively targeted a rare basal cell population, while preserving epithelial integrity. Using undifferentiated HNO-ALIs, we determined for the first time that Krt23+ activated basal cells (ABCs) are uniquely susceptible to RSV infection, a finding we confirmed in fully differentiated HNO-ALIs. Together, our findings show that RSV can infect the respiratory epithelium from the basolateral side by initially targeting a rare subset of basal cells before spreading apically to ciliated cells. Moreover, RSV/B/BA may have an advantage over RSV/A/ON in utilizing the basolateral infection route. These findings highlight an alternative RSV infection pathway and could be a potential mechanism for RSV spread to the lower airways. ImportanceUnderstanding the pathogenesis of RSV is essential to understanding and preventing acute and long-term sequelae from infection. The canonical understanding of RSV infection is that the virus infects and is restricted to the apical ciliated cells upon inhalation or fomite exposure. We demonstrate that an alternative route of infection - the basolateral route, can be utilized by RSV to infect the apical ciliated cells of the respiratory epithelium. We also show for the first time a novel difference in infectivity between the two contemporaneous RSV strains (RSV/A/ON and RSV/B/BA). In addition, we describe a rare basal subset-the Krt23+ activated basal cells that are uniquely susceptible to RSV thus expanding the known cellular tropism of RSV. Infection of basal cells can impact airway differentiation, homeostasis, and remodeling. Overall, our findings expand on the pathogenesis of RSV and indicate there are alternative mechanisms of infection and cell populations that are susceptible to RSV.

microbiology↗

bioRxiv2025

Evolutionary convergence of a Pyroptosis-Apoptosis crosstalk drives non-canonical inflammasome signalling.

The coordination of efficient immune responses to infections is essential to enable pathogen clearance and host survival. Cell death modalities are a crucial component of the innate immune system and are key to controlling intracellular and extracellular infections. Human caspase-4 and -5 are cysteine proteases activated upon intracellular detection of bacterial lipopolysaccharide (LPS) and triggers pyroptosis, a lytic and pro-inflammatory form of cell death. However, the interaction between these caspases and other cell death modalities remains poorly understood. Here, we build on evidence that caspase-4 can engage in crosstalk with the apoptotic executioner caspases-3 and -7. Our work validated caspase-3 and -7 as direct substrates of caspase-4 and -5, and demonstrated that this specificity was regulated by exosite interactions as opposed to the tetrapeptide. Using AlphaFold, we generated an interaction model between caspase-4 and executioner caspases-3 and -7. From this, we experimentally validated the importance of a hydrophobic interface on caspase-3 and -7 that engaged the caspase-4 exosite, enabling their recognition and cleavage. Importantly, this interface is not used by the apoptotic initiator caspase-8, which cleaved caspase-3 in a tetrapeptide-dependent manner. Our work highlights that inflammatory caspases have evolved a novel mechanism to coordinate crosstalk between pyroptotic and apoptotic signalling, and suggests that these pathways may synergise for the efficient amplification of cell death pathways.

biochemistry↗

bioRxiv2024

Making the Monitoring Framework of the Kunming-Montreal Global Biodiversity Framework fit for purpose.

The Kunming-Montreal Global Biodiversity Framework (GBF) is the most ambitious agreement on biodiversity conservation and sustainable use to date. It calls for a whole-of government and whole-of-society approach to halt and reverse biodiversity loss worldwide. The Monitoring Framework of the GBF lays out how Parties to the Convention on Biological Diversity (CBD) are expected to report their progress. A CBD expert group provided guidance on its implementation, including a gap analysis to identify the strengths and limitations of the indicators in the Monitoring Framework. We present the results of the gap analysis, highlight where more work is needed and provide recommendations on implementing and improving monitoring to allow effective and comprehensive tracking of the GBFs ambition. We find that with the headline and binary indicators, which Parties are required to use, the Monitoring Framework fully covers 19% of the GBFs ambition and partially covers an additional 40%. Including disaggregations of the headline indicators improves coverage to 22% fully and an additional 41% partially. Adding optional (component and complementary) indicators brings full coverage to 29% with an additional 47% partial coverage. No indicators are available for 12% of the GBF. In practice, the coverage of the Monitoring Framework will depend on which indicators (headline and binary as well as component and complementary) and disaggregations are used by countries. Disaggregations are particularly relevant to monitor the cross-cutting considerations defined under section C. Substantial investment is required to collect the necessary data to compute indicators, infer change, and effectively monitor progress. We highlight important next steps to progressively improve the efficacy of the Monitoring Framework.

ecology↗

bioRxiv2024

Leveraging the Red List of Ecosystems for national action on coral reefs through the Kunming-Montreal Global Biodiversity Framework

Countries have committed to conserving and restoring ecosystems after signing the Kunming-Montreal Global Biodiversity Framework (GBF). The IUCN Red List of Ecosystems (RLE) will serve as a headline indicator to track progress of countries towards achieving this goal, and to guide action across the GBFs targets. Using Kenyan coral reefs, we demonstrate how nations implementing the GBF, can use standardised estimates of ecosystem degradation from RLE assessments to support site-specific management decisions. We undertook a reef-by-reef analysis to evaluate the relative severity of decline of four key ecosystem components over the past 50-years: hard corals, macroalgae, parrotfish and groupers. Using the two benthic indicators, we also calculated standardised estimates of state to identify reef sites which maintain a better condition through time relative to adjacent sites. Over the past 50 years, Kenyas coral reefs have degraded across all four ecosystem components. At more than half the monitored sites both parrotfish and grouper abundance declined by more than 50%, while coral cover and macroalgae-coral ratio declined by at least 30%. This resulted in a Vulnerable threat status for coral reefs in Kenya based on degradation (under criterion D of the RLE). The temporal trends in coral cover revealed four sites which maintained an above average condition over their monitoring history (15-25 years). The results can guide management actions to contribute to at least nine of the 23 GBF targets. For example, we identified several sites with relatively healthy benthic and fish communities as candidate areas for protection measures under Target 3. We also found that Marine Protected Areas and Locally Managed Marine Areas, which restrict fishing and control gears, had lower declines in groupers compared to unmanaged areas, providing further evidence for their expansion. The RLE has a key role to play in monitoring and meeting the goals and targets of the Global Biodiversity Framework, and our work demonstrates how using the wealth of data within these assessments can inform local-scale ecosystem management and amplify the GBFs impact.

ecology↗

bioRxiv2020

Oligonucleotide Capture Sequencing of the SARS-CoV-2 Genome and Subgenomic Fragments from COVID-19 Individuals

The newly emerged and rapidly spreading SARS-CoV-2 causes coronavirus disease 2019 (COVID-19). To facilitate a deeper understanding of the viral biology we developed a capture sequencing methodology to generate SARS-CoV-2 genomic and transcriptome sequences from infected patients. We utilized an oligonucleotide probe-set representing the full-length genome to obtain both genomic and transcriptome (subgenomic open reading frames [ORFs]) sequences from 45 SARS-CoV-2 clinical samples with varying viral titers. For samples with higher viral loads (cycle threshold value under 33, based on the CDC qPCR assay) complete genomes were generated. Analysis of junction reads revealed regions of differential transcriptional activity and provided evidence of expression of ORF10. Heterogeneous allelic frequencies along the 20kb ORF1ab gene suggested the presence of a defective interfering viral RNA species subpopulation in one sample. The associated workflow is straightforward, and hybridization-based capture offers an effective and scalable approach for sequencing SARS-CoV-2 from patient samples.

genomics↗

bioRxiv2020

A Mental Health Paradox: Mental health was both a motivator and barrier to physical activity during the COVID-19 pandemic

The COVID-19 pandemic has impacted the mental health, physical activity, and sedentary behavior of citizens worldwide. Using an online survey with 1669 respondents, we sought to understand why and how by querying about perceived barriers and motivators to physical activity that changed because of the pandemic, and how those changes impacted mental health. Consistent with prior reports, our respondents were less physically active (aerobic activity, -11%, p <0.05; strength-based activity, -30%, p<0.01) and more sedentary (+11%, p<0.01) during the pandemic as compared to 6-months before. The pandemic also increased psychological stress (+22%, p <0.01) and brought on moderate symptoms of anxiety and depression. Respondents whose mental health deteriorated the most were also the ones who were least active (depression r = -.21, p<0.01; anxiety r = -.12, p<0.01). The majority of respondents were unmotivated to exercise because they were too anxious (+8%, p <0.01), lacked social support (+6%, p =<0.01), or had limited access to equipment (+23%, p <0.01) or space (+41%, p <0.01). The respondents who were able to stay active reported feeling less motivated by physical health outcomes such as weight loss (-7%, p<0.01) or strength (-14%, p<0.01) and instead more motivated by mental health outcomes such as anxiety relief (+14%, p <0.01). Coupled with previous work demonstrating a direct relationship between mental health and physical activity, these results highlight the potential protective effect of physical activity on mental health and point to the need for psychological support to overcome perceived barriers so that people can continue to be physically active during stressful times like the pandemic.

scientific communication and education↗

bioRxiv2020

Oligonucleotide capture sequencing of the SARS-CoV-2 genome and subgenomic fragments from COVID-19 individuals

microbiology↗

bioRxiv2019

Synaptotagmin 1 oligomers clamp and regulate different modes of neurotransmitter release

Synaptotagmin1 (Syt1) synchronises neurotransmitter release to action potentials acting as the fast Ca2+ release sensor and as the inhibitor (clamp) of spontaneous and delayed asynchronous release. Whilst the Syt1 Ca2+ activation mechanism has been well characterised, how Syt1 clamps transmitter release remains enigmatic. Here we show that C2B domain-dependent oligomerisation provides the molecular basis for the Syt1 clamping function. This follows from the investigation of a designed mutation (F349A), which selectively destabilises Syt1 oligomerisation. Using combination of fluorescence imaging and electrophysiology in neocortical synapses we show that Syt1F349A is more efficient than wild type Syt1 (Syt1WT) in triggering synchronous transmitter release but fails to clamp spontaneous and Synaptotagmin7 (Syt7)-mediated asynchronous release components both in rescue (Syt1-/- knock-out background) and dominant-interference (Syt1+/+ background) conditions. Thus we conclude that Ca2+-sensitive Syt1 oligomers, acting as an exocytosis clamp, are critical for maintaining the balance among the different modes of neurotransmitter release.

neuroscience↗

bioRxiv2018

Analog closed-loop modulation of hippocampal pyramidal cells dissociates gamma frequency and amplitude

Gamma-band oscillations are implicated in modulation of attention and integration of sensory information. The finding that cross-regional coherence varies with task and performance suggests a role for gamma oscillations in flexible communication among anatomically connected brain areas. How networks become entrained is incompletely understood. Specifically, it is unclear how the spectral and temporal characteristics of network oscillations can be altered on rapid timescales needed for efficient communication. We use closed-loop optogenetic modulation of principal cell excitability to interrogate the dynamical properties of hippocampal oscillations. Gamma frequency and amplitude can be modulated bi-directionally, and dissociated, by phase-advancing or delaying optogenetic feedback to pyramidal cells. Closed-loop modulation alters the synchrony rather than average frequency of action potentials, in principle avoiding disruption of population rate-coding of information. Modulation of phasic excitatory currents in principal neurons is sufficient to manipulate oscillations, suggesting that feed-forward excitation of pyramidal cells has an important role in determining oscillatory dynamics and the ability of networks to couple with one another.

neuroscience↗