Biology subjects

Harvey, M.

Publications and source records attributed to Harvey, M..

14 recordsLinked to original sources

bioRxiv2026

Medulloblastoma Forms Symbiotic Metabolic Partnerships with Macrophages to Establish Leptomeningeal Metastases

Leptomeningeal metastases are the primary source of morbidity and mortality for pediatric medulloblastoma patients. Due to limited surgical sampling of metastases in patients, little is understood of the mechanisms of metastasis. Here, we identify biologically distinct quiescent small metastases (designated as micrometastases) and mitotically active larger metastases (macrometastases). Macrometastases are more metabolically active than micrometastases and contain higher levels of lipids, particularly cholesterol. Macrometastases secrete CXCL12, which attracts lipid-laden macrophages into the tumor. Lipid-laden macrophages upregulate the cholesterol transporter ABCG1, promoting the efflux of free cholesterol, which is then taken up by tumor cells via the HDL receptor SCARB1. CXCL12-driven macrophage recruitment and exogenous cholesterol are sufficient and necessary to drive progression of medulloblastoma leptomeningeal metastases in vivo. High fat diets drive metastatic progression in vivo. Dietary or pharmacological interventions targeting the CXCL12-SCARB1-cholesterol axis represent therapeutic strategies to either prevent or treat medulloblastoma leptomeningeal metastases.

cancer biology↗

bioRxiv2026

When More Is Not Better: Increased Motor Cortex Recruitment In Older Adults Is Associated With Performance Decline During High-Demand Cognitive-Motor Tasks

Age-related changes in brain structure and function lead to reorganisation in neural activity during cognitive-motor tasks. A central question is whether increased brain activity in older adults reflects compensatory mechanisms that help maintain performance, or inefficient recruitment due to neural dedifferentiation. In this context, the Compensation-Related Utilization of Neural Circuits Hypothesis (CRUNCH) proposes that older adults recruit more brain resources as task demands rise, but reach a limit beyond which this no longer supports performance. This study examined brain activity changes in older adults in response to increased cognitive-motor task demands. Twenty-one right-handed older adults performed an Action Selection (AS) task with three difficulty levels during functional MRI. Behavioural performance declined with increasing task difficulty. Whole-brain analyses revealed that higher task complexity was associated with increased activation in sensorimotor and prefrontal regions, particularly the left dorsolateral prefrontal cortex (DLPFC) and left premotor cortex (PMd). Importantly, higher activity in subcortical regions (caudate nucleus) was associated with better performance at lower difficulties, while greater activation in cortical motor areas (primary motor cortex (M1), and the supplementary motor area (SMA)) was linked to worse performance at high difficulty. Additionally, greater increases in sensorimotor activity (M1, PMd, DLPFC) across difficulties correlated with greater declines in performance, supporting the notion of inefficient resource recruitment. Together, the findings support a novel hypothesis, compatible with CRUNCH, of a subcortical to cortical shift (SCOS) with increasing cognitive-motor demand, where the transition from efficient subcortical processing to over-reliance on cortical motor areas may contribute to performance decline in ageing.

neuroscience↗

bioRxiv2025

Live-Cell Chemoproteomic Profiling Identifies the Uncharacterised Protein YbaA as a Direct Target of Ciprofloxacin in Escherichia coli

Fluoroquinolone antibiotics, such as ciprofloxacin, are important broad-spectrum agents for a range of bacterial infections; however, fluoroquinolone usage is increasingly challenged by the emergence of resistance. Ciprofloxacin resistance mechanisms include mutations in the antibiotic target DNA gyrase, downregulation of porins required for bacterial cell penetration, and upregulation of efflux pumps to expel the antibiotic. However, new pathways driving bacterial tolerance to fluoroquinolones are still being discovered, suggesting that additional ciprofloxacin-binding proteins may exist in bacteria. In this study, we report the use of affinity-based protein profiling (AfBPP) with photo-crosslinking chemical probes to identify protein binding partners of ciprofloxacin in live E. coli cells. AfBPP identified novel ciprofloxacin binding proteins including YjdN and YbaA, whose molecular functions are as yet unannotated. Target engagement was validated using genetic knockout and biophysical binding assays, and key interactions identified in the ciprofloxacin binding site of YbaA. Collectively, this study demonstrates that additional and previously unreported biological interactions can exist for well-established antibiotics, and provides methodology to identify and interrogate these interactions in detail.

microbiology↗

bioRxiv2025

An effector from the potato late blight pathogen bridges ENTH-domain protein TOL9a to an activated helper NLR to suppress immunity

Pathogens counteract central nodes of NLR immune receptor networks to suppress immunity. However, the mechanisms by which pathogens hijack helper NLR pathways are poorly understood. Here, we show that an effector from the potato late blight pathogen Phytophthora infestans bridges the host protein NbTOL9a, a putative member of the host ESCRT pathway, to a helper NLR to suppress immunity. In this work, we solved the crystal structure of the RXLR-LWY effector AVRcap1b in complex with the ENTH domain of NbTOL9a. The structure revealed that unlike other RXLR-LWY effectors, AVRcap1b has a novel L-shaped fold that defines a new structural family of effectors in the Phytophthora genus. Moreover, we defined the AVRcap1b/NbTOL9a binding interface and designed effector mutants that dont bind NbTOL9a, impairing immune suppression. This indicates that ENTH binding is required for full virulence activity of this effector. Lastly, we show that AVRcap1b associates specifically with activated NbNRC2 independently of NbTOL9a binding. This suggests that the effector functions as a bridge that interconnects NbNRC2 with the NbTOL9a pathway. These results illustrate an unprecedented pathogen mechanism to hijack helper NLR pathways and suppress immunity.

plant biology↗

bioRxiv2025

Age differences in motivation drive performance during the sustained attention to response task

Young and older adults prioritise speed and accuracy differently during sustained attention tasks. While older adults generally show a preference of accuracy over speed, this is not always the case. The underlying factor behind this inconsistency may be motivational differences, with older participants compensating for a speed disadvantage with increased intrinsic motivation to perform well. We investigated this in a pre-registered study, using the Sustained aAttention to Response Task (SART) in young (n = 25, mean age = 19) and older adults (n = 25, mean age = 69.5). We matched participant accuracy by titrating response window length. Both groups achieved similar performance and strategy during the titration, enabling a comparison without confounds resulting from differences in default age-specific strategies. All participants were then monetarily encouraged to perform better in terms of accuracy. Both groups responded with an adaptive strategy of slowed reaction times and enhanced accuracy, but the young participants improved much more, outperforming older adults, and reversing the speed-accuracy strategies that are typically observed. In addition, older participants reported higher baseline levels of motivation alongside a reduced motivation to alter performance for money. So, while the older participants could match young participant performance in titration due to their higher baseline motivational levels, the young participants improved much more than older adults in response to the monetary incentive. From these findings we argue that older adults are intrinsically motivated to do well on tasks whereas younger age groups perform optimally only after incentivisation.

neuroscience↗

bioRxiv2024

EEG markers of vigilance, task-induced fatigue and motivation during sustained attention: Evidence for decoupled alpha- and beta-signatures

Reduced vigilance can be captured in measures of attentional lapses in sustained attention tasks, but just how these lapses relate to task-induced fatigue and motivation to maintain optimal performance is unclear. We used the sustained attention to response task (SART) to induce fatigue, and manipulated motivation levels for the last block of the task in young and older participants (N = 34), while recording EEG to track electrophysiological markers of vigilance change, fatigue and motivation. Despite significant increases in subjective fatigue and mind wandering over 45 minutes, no vigilance decline was observed. However, the age groups differed markedly in their response strategies from the outset (adopting distinct speed-accuracy trade-off strategies) with faster/more erroneous responses in the younger and slower/more accurate responses in the older participants. The subjective rises in fatigue/mind wandering were coupled with an increase in pre-stimulus alpha-power, whereas the post-stimulus activity revealed two distinguishable beta signatures: a fronto-central topography as a marker of response strategy and a fronto-parietal distribution modulated by motivation per se. Our results thus show three distinct neural patterns underpinning the effects of fatigue, response strategy and motivation and suggest a (motivational) cognitive control mechanism behind resetting of performance decrement, independent of persistent fatigue.

neuroscience↗

bioRxiv2024

Delineating In-Vivo T1-Weighted Intensity Profiles Within the Human Insula Cortex Using 7-Tesla MRI

The integral role of the insula cortex in sensory and cognitive function has been well documented in humans, and fine anatomical details characterising the insula have been extensively investigated ex-vivo in both human and non-human primates. However, in-vivo studies of insula anatomy in humans (in general), and within-insula parcellation (in particular) have been limited. The current study leverages 7 Tesla magnetic resonance imaging to delineate cortical depth intensity profiles within the human cortex. Our analysis revealed two separate clusters of relatively high and low signal intensity across the insula cortex located in three distinct compartments within the posterior, anterior-inferior, and middle insula. The posterior and anterior-inferior compartments are characterised by elevated T1-weighted signal intensities, contrasting with lower intensity observed in the middle insular compartment, compatible with ex-vivo studies. Importantly, the detection of the high T1-weighted anterior cluster is determined by the choice of brain atlas employed to define the insular ROI. We obtain reliable in-vivo within-insula parcellation at the individual and group levels, across two separate cohorts acquired in two separate sites (n1 = 21, Glasgow, UK; n2 = 101, Amsterdam, NL). Results are further confirmed by deriving cortical depth dependent profiles from T1Map and R1Map images. These results reflect new insights into the insula anatomical structure, in-vivo, while highlighting the use of 7 Tesla in neuroimaging with potential implications for individualised medicine approaches. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/605123v3_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1c27244org.highwire.dtl.DTLVardef@dbd256org.highwire.dtl.DTLVardef@1ce44f6org.highwire.dtl.DTLVardef@11183d0_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Probing sustained attention and fatigue across the lifespan

Trait fatigues reflects tiredness that persists throughout a prolonged period, whereas state fatigue is defined to be short term after "intense and/or prolonged effort". We investigated the impact of prolonged sustained attention (using the SART task) on both trait and state fatigue levels in the general population. A JsPsych online version of the SART task was undertaken by 115 participants, stratified across the whole adult lifespan. While pre-task trait fatigue was a strong indicator of the initial state fatigue levels, undergoing the task itself induced an increase in reported subjective state fatigue, as well as reduced energy. Consistent with this finding, greater subjective state fatigue levels were associated with reduced accuracy. In addition, age was the best predictor of inter-participant accuracy (the older the participants, the greater the accuracy), and learning (i.e., task duration reducing reaction times). Moreover, a ceiling effect occurred where participants with higher trait fatigue did not experience greater state fatigue changes relative to those with low trait scores. In summary, we found improved accuracy in older adults, as well as a tight coupling between state fatigue and SART performance decline (in an online environment). The findings warrant further investigation into fatigue as a dynamic, task-dependent state and into SART task performance as an objective measure and inducer of fatigue.

neuroscience↗

bioRxiv2022

Optogenetic activation of visual thalamus generates artificial visual percepts

The lateral geniculate nucleus (LGN), a retinotopic relay center where visual inputs from the retina are processed and relayed to the visual cortex, has been proposed as a potential target for artificial vision. At present, it is unknown whether optogenetic LGN stimulation is sufficient to elicit behaviorally relevant percepts and the properties of LGN neural responses relevant for artificial vision have not been thoroughly characterized. Here, we demonstrate that tree shrews pretrained on a visual detection task can detect optogenetic LGN activation using an AAV2-CamKII-ChR2 construct and readily generalize from visual to optogenetic detection. We also characterize how amplitude and frequency of optogenetic stimulation affect behavioral performance. Given the importance of temporal stimulation parameters, we also study tree shrew behavioral ability to discriminate among pairs of visual flicker frequencies and demonstrate performance transfer among related discrimination problems as well as limitations. Neural recordings in LGN and primary visual cortex (V1) examining two flicker discriminations reveal that while LGN neurons multiplex information about temporal stimulation discriminations, V1 neurons explicitly encode information about one or the other discriminations but not both. Our findings confirm the LGN as a potential target for visual prosthetics and introduce a distinction in stimulus encoding between thalamic and cortical representations that could be of fundamental importance in artificial vision.

neuroscience↗

bioRxiv2022

Prediction error signals in anterior cingulate cortex drive task-switching

Task-switching is a fundamental cognitive ability that allows animals to update their knowledge of current rules or contexts. Detecting discrepancies between predicted and observed events is essential for this process. However, little is known about how the brain computes cognitive prediction-errors and whether neural prediction-error signals are causally related to task-switching behaviours. Here we trained mice to use a prediction-error to switch, in a single trial, between responding to the same stimuli using two distinct rules. Optogenetic silencing and un-silencing, together with widefield and two-photon calcium imaging revealed that the anterior cingulate cortex (ACC) was specifically required for this rapid task-switching, but only when it exhibited neural prediction-error signals. These prediction-error signals were projection-target dependent and were larger preceding successful behavioural transitions. An all-optical approach revealed a disinhibitory interneuron circuit required for successful prediction-error computation. These results reveal a circuit mechanism for computing prediction-errors and transitioning between distinct cognitive states.

neuroscience↗

bioRxiv2019

Air mass source determines airborne microbial diversity at the ocean-atmosphere interface of the Great Barrier Reef marine ecosystem

The atmosphere is the least understood biome on Earth despite its critical role as a microbial transport medium. The influence of surface cover on composition of airborne microbial communities above marine systems is unclear. Here we report evidence for a dynamic microbial presence at the ocean-atmosphere interface of a major marine ecosystem, the Great Barrier Reef, and identify that recent air mass trajectory over an oceanic or continental surface associated with observed shifts in airborne bacterial and fungal diversity. Relative abundance of shared taxa between air and coral microbiomes varied between 2.2-8.8% and included those identified as part of the core coral microbiome. We propose that this variable source of atmospheric inputs may in part contribute to the diverse and transient nature of the coral microbiome.

microbiology↗

bioRxiv2018

Basal Forebrain Deep Brain Stimulation Impacts the Regulation of Extracellular Vesicle Related Proteins in the Rat Brain

Extracellular vesicle (EV) signaling has attracted considerable attention in recent years because EVs play a key role in long distance cellular communication functions. EV studies have begun to reveal aspects of physiological and physiopathological regulation in numerous applications, although many areas remain to date largely unexplored. Deep brain stimulation (DBS) has shown remarkable therapeutic benefits of patients with neuropsychiatric disorders, but despite of the long and successful history of use, the mechanisms of action on neural ensemble activity are not yet fully understood. Here we explore how DBS of the basal forebrain impacts EV signaling in the rat brain. We employed differential centrifugations to isolate the EVs prefrontal cortex (PFC), hippocampus and striatum. We then performed quantitative analysis of EV-associated proteins using an MS-based proteomics method. We identified a considerable number of EV-associated proteins are modulated by DBS in three brain regions, some of which have been previously linked with central nervous system disorders. Particularly, neurofilament proteins NFL and NFM were both significantly changed in EVs of PFC, hippocampus and striatum after DBS stimulation compared with controls. The SOD1 protein, associated previously with neurodegenerative diseases, was significantly increased only in PFC. Our study is the first, to our knowledge, to use EV protein analysis to examine DBS effects on brain physiological regulation. Our findings open an entirely new perspective on brain area specific DBS effects.

neuroscience↗

bioRxiv2016

Habitat preference predicts genetic diversity and population divergence in Amazonian birds

The ecological traits of organisms may predict important evolutionary parameters such as genetic diversity, population genetic structure, and demographic history. Making these ecological-evolutionary links is difficult because robust, comparable genetic estimates are required from many species with differing ecologies. In Amazonian birds, differences in habitat preference are an important component of ecological diversity. A subset of Amazonian birds is restricted to forest edge and open forest along floodplains, whereas another subset occurs only in the interior of tall, upland forest. Here, we examine the link between habitat and evolutionary metrics using 20 pairs of closely related and co-distributed bird species in which one member of the pair occurs primarily in forest edge and floodplains, and the other occurs in upland forest interior. We use standardized geographic sampling and genomic data from the same set of 2,416 independent markers to estimate genetic diversity, population structure, and demographic history in each species. We find that species of upland forest have higher genetic diversity, greater divergence across the landscape, more genetically distinct populations, and deeper gene histories than floodplain species. Our results reveal that species ecology in the form of habitat preference is an important predictor of genetic diversity and divergence and suggest that floodplain and upland avifaunas in the Amazon may be on separate evolutionary trajectories and require different conservation strategies.

evolutionary biology↗

bioRxiv2016

A positive association between population genetic differentiation and speciation rates in New World birds

Although an implicit assumption of speciation biology is that population differentiation is an important stage of evolutionary diversification, its true significance remains largely untested. If population differentiation within a species is related to its speciation rate over evolutionary time, the causes of differentiation could also be driving dynamics of organismal diversity across time and space. Alternatively, geographic variants might be short-lived entities with rates of formation that are unlinked to speciation rates, in which case the causes of differentiation would have only ephemeral impacts. Combining population genetics datasets including 17,746 individuals from 176 New World bird species with speciation rates estimated from phylogenetic data, we show that the population differentiation rates within species predict their speciation rates over long timescales. Although relatively little variance in speciation rate is explained by population differentiation rate, the relationship between the two is robust to diverse strategies of sampling and analyzing both population-level and species-level datasets. Population differentiation occurs at least three to five times faster than speciation, suggesting that most populations are ephemeral. Population differentiation and speciation rates are more tightly linked in tropical species than temperate species, consistent with a history of more stable diversification dynamics through time in the Tropics. Overall, our results suggest investigations into the processes responsible for population differentiation can reveal factors that contribute to broad-scale patterns of diversity.

evolutionary biology↗