Biology subjects

Riley, E.

Publications and source records attributed to Riley, E..

9 recordsLinked to original sources

bioRxiv2026

Pupil size and pupil change correlate with distinct cortical neurochemical systems across the adult lifespan

Pupillometry is often used as a proxy for locus coeruleus (LC) activity, but whether this relationship changes across the lifespan is unknown, and important to establish due to the known change in LC biology with age. We collected simultaneous pupillometry and multi-echo fMRI in 89 adults aged 19-78 during a visual oddball task. Oddball-evoked pupillary responses were robust in all age groups but strongest in middle age. Oddball-evoked LC BOLD responses were relatively weak and did not predict individual pupillary responses, so we characterized pupil-BOLD coupling across the whole brain. Pupil size and its first derivative correlated with BOLD on distinct timescales (2.25 s and 5.00 s) and in distinct spatial patterns. Against 19 PET maps, derivative coupling correlated uniquely with norepinephrine transporter (NET) density, and size-unique coupling with -opioid (MOR) and cannabinoid CB1 density. Only pupil derivative-specific relationships with BOLD activity (both extent of coupling and association with NET) weakened with age, though both remained significant; other pupil-BOLD relationships did not differ with age. Pupil size and pupil change therefore carry different information about cortical activity throughout the lifespan.

neuroscience↗

bioRxiv2025

Vagal nerve stimulation alters task-evoked pupillary responses in older adults but not younger adults in a single-blind sham-controlled crossover trial

IntroductionThe locus coeruleus (LC) undergoes age-related changes and is involved in Alzheimers disease pathogenesis. Vagal nerve stimulation (VNS) may modulate LC activity and could be used therapeutically, but age-related differences in VNS responses remain unexplored. MethodsWe used a single-blind, sham-controlled, crossover design in 41 participants (21 younger, 20 older adults). Participants completed a visual oddball task with pupillometry during transcutaneous auricular VNS (verum: cymba concha; sham: earlobe) with [~]30-minute washout between conditions. ResultsOlder adults showed smaller baseline pupil diameter but larger normalized task-evoked responses than younger adults a priori. VNS produced age-specific effects: older adults demonstrated increased tonic pupil size throughout stimulation and reduced oddball-evoked responses, with stronger effects with more current. Younger adults showed no consistent VNS effects. DiscussionVNS affects LC-related physiological measures differently across age groups, with older adults showing more robust responses. These age-specific effects may reflect different baseline LC activity states.

neuroscience↗

bioRxiv2025

Advancing genetic engineering in the plant growth-promoting agricultural bacterium Azospirillum brasilense.

Azospirillum brasilense is an important plant-growth promoting bacterium found in the rhizosphere and used extensively in commercial agriculture. It is an attractive candidate for use in the development of novel crop interventions, such as the targeted delivery of plant hormones and similar compounds to the roots, shoots or leaves, or the introduction of smart bacterial sensors and actuators in the rhizosphere. In order to be able to engineer A. brasilense with these novel and complex behaviours, we require a collection of predictable and reliable genetic parts, consisting of constitutive and inducible promoters, terminators, and a stable expression plasmid. To date, such a genetic toolkit does not exist for the genus. In this work, for the first time we have designed and tested a synthetic constitutive promoter library with a wide-range of transcriptional strengths, a tightly-regulated inducible promoter with a non-metabolisable inducer, strong Rho-independent transcriptional terminators and synthetic small RNAs for post-transcriptional regulation.. We have adapted them for use in a one-pot assembly method and demonstrated their utility in the overproduction of the important plant hormone, indole 3-acetic acid (IAA).

synthetic biology↗

bioRxiv2023

Locus coeruleus neuromelanin accumulation and dissipation across the lifespan

The pigment neuromelanin, produced in the locus coeruleus (LC) as a byproduct of catecholamine synthesis, gives the "blue spot" its name, and both identifies LC neurons and is thought to play an important yet complex role in normal and pathological aging. Using neuromelanin-sensitive T1-weighted turbo spin echo MRI scans we characterized volume and neuromelanin signal intensity in the LC of 96 participants between the ages of 19 and 86. Although LC volume did not change significantly throughout the lifespan, LC neuromelanin signal intensity increased from early adulthood, peaked around age 60 and precipitously declined thereafter. Neuromelanin intensity was greater in the caudal relative to rostral extent and in women relative to men. With regard to function, rostral LC neuromelanin intensity was associated with fluid cognition in older adults (60+) only in those above the 50th percentile of cognitive ability for age. The gradual accumulation of LC neuromelanin across the lifespan, its sudden dissipation in later life, and relation to preserved cognitive function, is consistent with its complex role in normal and pathological aging.

neuroscience↗

bioRxiv2023

Attention-dependent coupling with forebrain and brainstem neuromodulatory nuclei changes across the lifespan

Attentional states continuously reflect the predictability and uncertainty in ones environment having important consequences for learning and memory. Beyond well known cortical contributions, rapid shifts in attention are hypothesized to also originate from deep nuclei, such as the basal forebrain (BF) and locus coeruleus (LC) neuromodulatory systems. These systems are also the first to change with aging. Here we characterized the interplay between these systems and their regulation of afferent targets - the hippocampus (HPC) and posterior cingulate cortex (PCC) - across the lifespan. To examine the role of attentional salience on task-dependent functional connectivity, we used a target-distractor go/no go task presented during functional MRI. In younger adults, BF coupling with the HPC, and LC coupling with the PCC, increased with behavioral relevance (targets vs distractors). Although the strength and presence of significant regional coupling changed in middle age, the most striking change in network connectivity was in old age, such that in older adults BF and LC coupling with their cortical afferents was largely absent and replaced by stronger interconnectivity between LC-BF nuclei. Overall rapid changes in attention related to behavioral relevance revealed distinct roles of subcortical neuromodulatory systems. The pronounced changes in functional network architecture across the lifespan suggest a decrease in these distinct roles, with deafferentation of cholinergic and noradrenergic systems associated with a shift towards mutual support during attention guided to external stimuli. Significance statementChanges in attentional control across the lifespan may originate from cortical control networks or subcortical neuromodulatory systems, which are the first sites of age-related neuropathology. In young adults, we demonstrated functional coupling of the basal forebrain with the hippocampus, and locus coeruleus with the posterior cingulate cortex varies with task relevance. This coupling changed in middle age and most strikingly in older adults. In old age, task-dependent coupling between the locus coeruleus and basal forebrain was the predominant connection remaining within the observed network. Older adults exhibit reduced subcortical-cortical connectivity, consistent with a relative neuromodulatory deafferentation, replaced by subcortical-subcortical deep nuclear connectivity. This alteration in noradrenergic and cholinergic signaling has important implications for attention and memory formation and neurocognitive aging.

neuroscience↗

bioRxiv2019

Estimates of locus coeruleus function with functional magnetic resonance imaging are influenced by localization approaches and the use of multi-echo data

The locus coeruleus (LC) plays a central role in regulating human cognition, arousal, and autonomic states. Efforts to characterize the LCs function in humans using functional magnetic resonance imaging have been hampered by its small size and location near a large source of noise, the fourth ventricle. We tested whether the ability to characterize LC function is improved by employing neuromelanin-T1 weighted images (nmT1) for LC localization and multi-echo functional magnetic resonance imaging (ME-fMRI) for estimating intrinsic functional connectivity (iFC). Analyses indicated that, relative to a probabilistic atlas, utilizing nmT1 images to individually localize the LC increases the specificity of seed time series and clusters in the iFC maps. When combined with independent components analysis (ME-ICA), ME-fMRI data provided significant gains in the temporal signal to noise ratio relative to denoised single-echo (1E) data. The effects of acquiring nmT1 images and ME-fMRI data did not appear to only reflect increases in power: iFC maps for each approach only moderately overlapped. This is consistent with findings that ME-fMRI offers substantial advantages over 1E data acquisition and denoising. It also suggests that individually identifying LC with nmT1 scans is likely to reduce the influence of other nearby brainstem regions on estimates of LC function.\n\nHighlightsO_LIManual tracing of locus coeruleus increased specificity of seed time series\nC_LIO_LIManual tracing of locus coeruleus increased specificity of intrinsic connectivity\nC_LIO_LIMulti-echo fMRI increased temporal signal-to-noise ratio compared to single-echo fMRI\nC_LIO_LIConnectivity maps across methodologies overlapped only moderately\nC_LIO_LIMeasurement of LC function benefits from multi-echo fMRI and tracing ROIs\nC_LI

neuroscience↗

bioRxiv2018

Immune profiling of cord blood after prolonged rupture of membranes.

We hypothesised that foetal immune responses to an infectious challenge may be detected by genome-wide transcriptional profiling of cord blood. In order to test this hypothesis, we sought to identify transcriptomic changes in post-natal cord blood samples following prolonged pre-labour rupture of membranes (PROM) as a surrogate for increased risk of infection. By comparison to controls we found increased levels of blood transcripts in a subset of prolonged PROM cases, significantly enriched for innate immune system signalling pathways. These changes were idiosyncratic, suggesting qualitative and quantitative variation in foetal immune responses which may reflect differences in exposure and/or in host genetics. Our data support the view that PROM represents an infection risk to the foetus. In addition, we propose that cord blood transcriptional profiling offers exciting opportunities to identify immune correlates of clinical outcome following potential in utero exposures to infection. These may be used to elucidate the mechanisms of immunological protection and pathology in the foetus and identify biomarkers to stratify the risk of adverse outcomes.

immunology↗

bioRxiv2018

Estimating parasite load dynamics to reveal novel resistance mechanisms to human malaria

Improved methods are needed to identify host mechanisms which directly protect against human infectious diseases in order to develop better vaccines and therapeutics1,2. Pathogen load determines the outcome of many infections3, and is a consequence of pathogen multiplication rate, duration of the infection, and inhibition or killing of pathogen by the host (resistance). If these determinants of pathogen load could be quantified then their mechanistic correlates might be determined. In humans the timing of infection is rarely known and treatment cannot usually be withheld to monitor serial changes in pathogen load and host response. Here we present an approach to overcome this and identify potential mechanisms of resistance which control parasite load in Plasmodium falciparum malaria. Using a mathematical model of longitudinal infection dynamics for orientation, we made individualized estimates of parasite multiplication and growth inhibition in Gambian children at presentation with acute malaria and used whole blood RNA-sequencing to identify their correlates. We identified novel roles for secreted proteases cathepsin G and matrix metallopeptidase 9 (MMP9) as direct effector molecules which inhibit P. falciparum growth. Cathepsin G acts on the erythrocyte membrane, cleaving surface receptors required for parasite invasion, whilst MMP9 acts on the parasite. In contrast, the type 1 interferon response and expression of CXCL10 (IFN-{gamma}-inducible protein of 10 kDa, IP-10) were detrimental to control of parasite growth. Natural variation in iron status and plasma levels of complement factor H were determinants of parasite multiplication rate. Our findings demonstrate the importance of accounting for the dynamic interaction between host and pathogen when seeking to identify correlates of protection, and reveal novel mechanisms controlling parasite growth in humans. This approach could be extended to identify additional mechanistic correlates of natural- and vaccine-induced immunity to malaria and other infections.

systems biology↗

bioRxiv2016

A structural variant encoding hybrid glycophorins is associated with resistance to severe malaria

Plasmodium falciparum invades human red blood cells by a series of interactions between host and parasite surface proteins. Here we analyse whole genome sequence data from worldwide human populations, including 765 new genomes from across sub-Saharan Africa, and identify a diverse array of large copy number variants affecting the host invasion receptor genes GYPA and GYPB. We find that a nearby reported association with severe malaria is explained by a complex structural variant that involves the loss of GYPB and gain of two hybrid genes, each with a GYPB extracellular domain and GYPA intracellular domain. This variant reduces the risk of severe malaria by 40% and has recently risen in frequency in parts of Kenya. We show that the structural variant encodes the Dantu blood group antigen, and therefore a serologically distinct red cell phenotype. These findings demonstrate that structural variation of red blood cell invasion receptors is associated with natural resistance to P. falciparum malaria.

genomics↗