Biology subjects

Jones, E. J.

Publications and source records attributed to Jones, E. J..

At least 19 recordsLinked to original sources

bioRxiv2026

Acute caffeine ingestion differentially alters motor unit behaviour during submaximal and fatiguing contractions

Background: Caffeine is widely used as an ergogenic aid, yet its effect on neuromuscular function remains heterogeneous across exercise conditions. Although caffeine is known to enhance central nervous system excitability through adenosine receptor antagonism, the extent to which these effects modify spinal motor output remains unclear. Therefore, the present study aimed to characterise acute caffeine-induced alterations in neuromuscular properties during submaximal and sustained fatiguing contractions of the knee extensors. Methods: Seventeen healthy adults completed a randomised, placebo-controlled crossover study (3 mg/kg caffeine). Circulating serum caffeine concentrations were periodically quantified, while motor unit (MU) discharge behaviour, and delta F were derived from high-density surface electromyography. Statistical significance was set at p = 0.05. Results: No intervention effects were observed for MVC, force steadiness, or time to task failure (all p > 0.05). During graded contractions, vastus lateralis MU discharge rate was higher under caffeine (p < 0.001), and discharge variability was lower (p = 0.016). Recruitment and derecruitment thresholds were significantly greater under caffeine at 50% MVC (both p < 0.012), whereas paired MU analyses of delta F was unchanged (p = 0.083). During sustained contractions, caffeine altered fatigue-related trajectories of both MU discharge and discharge variability (intervention * phase interaction, p < 0.011). Conclusions: Acute caffeine ingestion alters motor unit behaviour without enhancing maximal force or fatigue resistance. These effects vary with contraction intensity and fatigue state but are not accompanied by a detectable change in discharge rate hysteresis in the vastus lateralis.

physiology↗

bioRxiv2026

Systemically delivered Bacteroides thetaiotaomicron-derived bacterial extracellular vesicles inhibit primary and metastatic melanoma growth

The gut microbiome can contribute to anti-tumour immunity and cancer therapy responses, but translating live microbe-based interventions remains challenging due to safety, controllability, and delivery constraints. Bacterial extracellular vesicles (BEVs) are an attractive cell-free alternative, as they package bacterial cargo into a nanoscale format capable of host-cell engagement, immunological activation, and systemic distribution. Here, we investigated the anti-tumour potential of BEVs derived from the human gut commensal Bacteroides thetaiotaomicron (Bt). We show that delivery route is a major determinant of efficacy. Intravenous, but not intraperitoneal, administration produced robust anti-tumour activity in a B16F10 melanoma mouse model. Intravenously delivered Bt BEVs suppressed primary tumour growth in a dose-dependent manner and reduced metastatic outgrowth in the lung. Bt BEVs did not directly impair tumour-cell viability in vitro, but they activated NF-{kappa}B and Toll-like receptor signalling in innate immune reporter systems and localised to tumour tissue following systemic administration. Together, these data support a model in which Bt BEVs act via host immune modulation rather than direct tumour cytotoxicity. These findings identify naturally produced commensal-derived Bt BEVs as a potential microbial therapeutic modality and as an alternative to the use of live bacterial administration in cancer therapy.

cancer biology↗

bioRxiv2025

Task Complexity and Limb Dominance Modulate the Effects of Ageing on Neuromuscular Function

BackgroundNeuromuscular function is critical for independence in ageing, yet asymmetries between dominant and non-dominant limbs, arising from central or peripheral mechanisms, are not well understood. This study examined age- and limb-related differences and motor unit (MU) firing behaviour of the vastus lateralis under tasks of varying difficulty. MethodsTwenty-one young (22 {+/-} 4 years; 15M, 6F) and seventeen older adults (74 {+/-} 5 years; 12M, 5F) performed constant and variable force unilateral isometric knee extensions. In both limbs, high-density surface electromyography signals were decomposed into MU spike trains. Force control and MU firing properties were analysed using multilevel mixed-effects regression models. ResultsOlder adults showed reduced maximal muscle strength (p<0.001) and increased force tracking error (p=0.008), MU firing rate (MUFR) was significantly lower in older adults during constant contractions (p = 0.001) and trended toward lower during variable contractions (p=0.061). MUFR variability showed a significant Leg x AgeGroup interaction (p<0.001); older adults had greater variability in non-dominant legs, while younger adults showed the opposite. With variable force contractions in both age groups, MUFR was higher during ascending segments with greater variability during descending segments. ConclusionNeuromuscular ageing involves asymmetric adaptations rather than a uniform decline, with leg dominance effects become more pronounced under variable force modulation. Task difficulty amplifies these asymmetries, underscoring the need to consider limb-specific neural control in age-related motor assessments.

physiology↗

bioRxiv2025

Rapamycin exerts its geroprotective effects in the ageing human immune system by enhancing resilience against DNA damage

mTOR inhibitors such as rapamycin are among the most robust life-extending interventions known, yet the mechanisms underlying their geroprotective effects in humans remain incompletely understood. At non-immunosuppressive doses, these drugs are senomorphic, i.e. they mitigate cellular senescence, but whether they protect genome stability itself has been unclear. Given that DNA damage is a major driver of immune ageing, and immune decline accelerates whole-organism ageing, we tested whether mTOR inhibition enhances genome stability. In human T cells exposed to acute genotoxic stress, we found that rapamycin and other mTOR inhibitors suppressed senescence not by slowing protein synthesis, halting cell division, or stimulating autophagy, but by directly reducing DNA lesional burden and improving cell survival. Ex-vivo analysis of aged immune cells from healthy donors revealed a stark enrichment of markers for DNA damage, senescence, and mTORC hyperactivation, suggesting that human immune ageing may be amenable to intervention by low-dose mTOR inhibition. To test this in vivo, we conducted a placebo-controlled experimental medicine trial in older adults administered with low-dose rapamycin. p21, a marker of DNA damage-induced senescence, was significantly reduced in immune cells from the rapamycin compared to placebo group. These findings reveal a previously unrecognised role for mTOR inhibition: direct genoprotection. This mechanism may help explain rapamycins exceptional geroprotective profile and opens new avenues for its use in contexts where genome instability drives pathology, ranging from healthy ageing, clinical radiation exposure, and even the hazards of cosmic radiation in space travel.

immunology↗

bioRxiv2025

Head before heart: cognitive empathy emerges before affective empathy in the developing brain

Empathy is crucial for social interactions across all cultures, and is foundational to establishing social cooperation and group ties in human societies. Challenging the current predominant view, we recently proposed that understanding others emotions (cognitive empathy) might emerge earlier than actually sharing those emotions (affective empathy) (Bulgarelli & Jones, 2023). Here we test this hypothesis by measuring which empathic component matures first during toddlerhood, a critical period for the development of broader social networks. Addressing this question is critical to understand the mechanisms through which caregivers scaffold empathy development. Traditional approaches are inadequate, as they rely on childrens verbal skills or unfamiliar scenarios that lack ecological validity. In this preregistered study, we employed a novel toddler-appropriate task to dissociate neural and physiological correlates of cognitive and affective empathy in N=90 3-to-6-year-olds using functional near-infrared spectroscopy (fNIRS) and simultaneous heart rate monitoring to identify internal markers of empathy. We found that brain regions supporting affective and cognitive empathy in young children resemble those observed in adults. Importantly, we showed an effect of age on network specialisation with brain activations of cognitive empathy stronger in younger compared to older preschoolers, and brain activations of affective empathy stronger in older compared to younger preschoolers. These results may provide the first evidence that cognitive empathy is engaged early and develops alongside or ahead of affective empathy in preschoolers, challenging existing models and suggesting a new framework for understanding the development of empathy. Significance statementEmpathy is a crucial social skill, consisting of an affective component--sharing emotion--and a cognitive component--conceptually understanding emotions. While to date it has been predominately accepted that the affective component develops earlier than the cognitive one, we recently proposed the opposite, which could have important implications for understanding the mechanisms that underpin social skills. Here we successfully developed a new task to dissociate physiological and neural markers of affective and cognitive empathy in N=90 preschoolers. We found that brain activations for cognitive empathy are stronger than for affective empathy in young children. This provide the first direct evidence for the earlier emergence of cognitive empathy, suggesting that scaffolding the understanding of others emotions may be crucial for empathy development.

neuroscience↗

bioRxiv2025

Epigenome-wide analysis reveals novel DNA methylation signatures significantly associated with the infant pupillary light reflex, a candidate intermediate phenotype for autism.

Autism is a highly heterogeneous neurodevelopmental condition, currently diagnosed based on behavioural characteristics. Candidate early intermediate phenotypes, such as the Pupillary Light Reflex (PLR), a reflexive constriction of the pupil in response to increased optical luminance, may provide insights into etiological factors and potential biomarkers, such as DNA methylation (DNAm), involved in the emergence of autism. We conducted epigenome-wide DNAm association analyses of 9-, 14-, 24-month PLR onset latency and constriction amplitude in a sample of 51 infants enriched for autism family history, using buccal DNA collected at 9-months. Our epigenome-wide analysis (EWAS) identified four stringently significant differentially methylated probes (p < 2.4 x 10-7) associated with cross-section PLR latency measurements at 14- and 24-months, and with 14-to 24-month PLR latency developmental change. Differentially methylated probes associated with PLR amplitude were identified, but at a less stringent discovery threshold (p < 5 x 10-5). Our region analyses identified several significant differentially methylated regions associated with both PLR latency and amplitude Downstream exploratory pathway analysis identified enrichment for multiple developmental biological processes, as well as several susceptibility genes to autism and related neurodevelopmental conditions including NR4A2, HNRNPU and NAV2. Our findings provide novel insight into the role of DNAm in PLR development and illuminate biological mechanisms underpinning altered PLR in infancy in emerging autism.

neuroscience↗

bioRxiv2024

Qualitative EEG abnormalities signal a shift towards inhibition-dominated brain networks. Results from the EU-AIMS LEAP studies

Qualitative EEG abnormalities are common in Autism Spectrum Disorder (ASD) and hypothesized to reflect disrupted excitation/inhibition balance. To test this, we recently introduced a functional measure of network-level E/I ratio (fE/I). Here, we applied fE/I and other EEG measures to alpha oscillations from source-reconstructed data in the EU-AIMS dataset (267 ASD, 209 controls). We analyzed these measures alongside qualitative EEG abnormalities ranging from slowing of activity to epileptiform patterns, aiming to replicate the findings from the SPACE-BAMBI study. EEG abnormalities were rare in adults and could not be statistically assessed. ASD children-adolescents with EEG abnormalities exhibited lower relative alpha power and fE/I compared to those without. However, EEG-abnormality scoring did not stratify the behavioral heterogeneity of ASD using clinical measures. Surprisingly, several controls also exhibited qualitative EEG abnormalities with a strikingly similar anatomical distribution of reduced fE/I, suggesting a shift towards inhibition-dominated network dynamics in sensory processing regions. The robustness of this association between EEG abnormalities and reduced fE/I was further supported by re-analysis of the SPACE-BAMBI study in source space. Stratification by the presence of EEG abnormalities and their effects on network activity may help understand neurodevelopmental physiological heterogeneity and the difficulties in implementing E/I targeting treatments in unselected cohorts.

neuroscience↗

bioRxiv2024

The spatial layout of antagonistic brain regions are explicable based on geometric principles

Brain activity emerges in a dynamic landscape of regional increases and decreases that span the cortex. Increases in activity during a cognitive task are often assumed to reflect the processing of task-relevant information, while reductions can be interpreted as suppression of irrelevant activity to facilitate task goals. Here, we explore the relationship between task-induced increases and decreases in activity from a geometric perspective. Using a technique known as kriging, developed in earth sciences, we examined whether the spatial organisation of brain regions showing positive activity could be predicted based on the spatial layout of regions showing activity decreases (and vice versa). Consistent with this hypothesis we established the spatial distribution of regions showing reductions in activity could predict (i) regions showing task-relevant increases in activity in both groups of humans and single individuals; (ii) patterns of neural activity captured by calcium imaging in mice; and, (iii) showed a high degree of generalisability across task contexts. Our analysis, therefore, establishes that antagonistic relationships between brain regions are topographically determined, a spatial analog for the well documented anti-correlation between brain systems over time. Significance StatementIt is well documented that brain activity changes in response to the demands of different situations, although what gives rise to the observed cortical activity patterns remains poorly understood. Using analytic tools from earth sciences, we examined whether the landscape of regional changes in activity emerge from a set of common topographical causes. Using only regions showing decreases in activity, we could predict the landscape of regions showing increases in activity using fMRI in humans and calcium imaging in mice. Our results suggest topographical principles determine the landscape of peaks and valleys in brain activity -- a spatial analog for the well documented anti-correlation between sets of brain regions over time.

neuroscience↗

bioRxiv2024

The impact of heterogeneous spatial autocorrelation on comparisons of brain maps

It is increasingly common to statistically compare brain maps to assess how spatially similar they are. However, statistical inference can be challenging due to the presence of spatial autocorrelation. Therefore, random permutation approaches based on null models are widely used to address this concern. Here, we show how that the presence of heterogeneity in the spatial autocorrelation across brain maps impacts the validity of statistical inference in common approaches for spatially correlated maps. Furthermore, we illustrate how a Bayesian spatial regression approach can be applied to compare functional and structural cortical brain maps, yielding valid statistical inferences even in the presence of heterogeneity. Explicitly modelling spatial properties provides more valid inferences about whole brain spatial maps allowing a wider and more sophisticated range of neurobiological questions to be answered about the relationship between brain maps than are possible with current approaches.

neuroscience↗

bioRxiv2023

Amphibian mast cells: barriers to deadly chytrid fungus infections

Global amphibian declines are compounded by deadly disease outbreaks caused by the chytrid fungus, Batrachochytrium dendrobatidis (Bd). Much has been learned about the roles of amphibian skin-produced antimicrobial components and microbiomes in controlling Bd, yet almost nothing is known about the roles of skin-resident immune cells in anti-Bd defenses. Mammalian mast cells reside within and serve as key immune sentinels in barrier tissues like skin. Accordingly, we investigated the roles of Xenopus laevis frog mast cells during Bd infections. Our findings indicate that enrichment of X. laevis skin mast cells confers significant anti-Bd protection and ameliorates the inflammation-associated skin damage caused by Bd infection. This includes a significant reduction in Bd-infected skin infiltration by neutrophils. Augmenting frog skin mast cells promotes greater mucin content within cutaneous mucus glands and protects frogs from Bd-mediated changes to their skin microbiomes. Mammalian mast cells are known for their production of the pleiotropic interleukin-4 (IL4) cytokine and our findings suggest that the frog IL4 plays a key role in conferring the effects seen following frog skin mast cell enrichment. Together, this work underlines the importance of amphibian skin-resident immune cells in anti-Bd defenses and illuminates a novel avenue for investigating amphibian host-chytrid pathogen interactions.

immunology↗

bioRxiv2023

Sex disparities in age-related neuromuscular decline: unveiling female susceptibility from early to late elderly

BackgroundFemales typically have a longer lifespan than males which is not matched by an improved healthspan, with older females having higher rates of frailty, characteristic of a sex specific degradation of the neuromuscular system. Several motor unit (MU) characteristics show sex-specific behaviour during mid-level contractions in healthy younger people, highlighting a potential influence of hormonal differences that may be augmented in older age. The purpose of this study was to investigate sex differences in physical performance and MU features of the aged human vastus lateralis (VL) from early to late elderly. MethodsThis study included 21 healthy older males (mean {+/-} SD, range: 67.2 {+/-} 7.6, 56 - 81 yrs) and 17 healthy older females (69.5 {+/-} 5.2, 60 - 78 yrs). Intramuscular electromyography data were collected from VL during standardised submaximal sustained contractions. Muscle size and physical performance characteristics were also measured. Multiple mixed-effects linear regression models with age considered were conducted and statistical significance was accepted when p<0.05. ResultsWhen compared to males, early to late elderly females had smaller cross-sectional area of VL (p<0.001), lower knee extensor torque (p<0.001) and poorer force steadiness (p=0.036), as well as higher MU firing rate (FR) (p=0.025) and greater MU FR variability (p=0.031). With progression from early to late elderly, both sexes showed decreased functional capacity at a similar rate. ConclusionFunctional deterioration occurs to a similar extent in both sexes from early to late elderly. However, throughout the majority of the elderly period males demonstrate a greater muscle size, strength, and functional performance. Older females have greater MUFR variability and worse force steadiness than older males. These findings help to address the lack of MU data in older females, and suggest earlier interventions are needed in older females to prevent functional deterioration and reduce the health-sex paradox within ageing humans.

physiology↗

bioRxiv2023

Objective assessment of visual attention in toddlerhood

Visual attention is an important mechanism through which children learn about their environment, and individual differences could substantially shape later development. Eyetracking provides a sensitive and scalable tool for assessing visual attention that has potential for objective assessment of child development, but to date the majority of studies are small and replication attempts are rare. This study investigates the feasibility of a comprehensive eye-tracking assessment of visual attention and introduces a shared data resource for the scientific community. Data from eight eyetracking tasks were collected from 350 term-born (166 females) 18-month-olds recruited as neonates http://www.developingconnectome.org/). Analyses showed expected condition effects for seven of eight tasks (p-values from <.001 to .04), an important indication of replicability. Consistent with some theoretical models of visual attention, structural equation modelling indicated participants performance could be explained by two factors representing social and non-social attention. Comprehensive eye-tracking batteries can objectively measure individual differences in core components of visual attention in large-scale toddlerhood studies. This is the first large-scale comprehensive study to present high-quality normative eye-tracking data from a large task battery in toddlers and make them freely available to the scientific community.

neuroscience↗

bioRxiv2023

Menstrual cycle associated alteration of vastus lateralis motor unit function

Estrogen and progesterone are the primary female sex hormones and have net excitatory and inhibitory effects, respectively, on neuronal function. Fluctuating concentrations across the menstrual cycle has led to several lines of research in relation to neuromuscular function, yet evidence from animal and cell culture models have yet to be demonstrated in human motor units (MU) coupled with quantification of circulating hormones. Intramuscular electromyography (iEMG) was applied to record MU potentials (MUP) and corresponding MUP trains (MUPT) from the vastus lateralis of eumenorrheic females during the early follicular, ovulation and mid luteal phases of the menstrual cycle, alongside assessments of neuromuscular performance. Multi-level regression models were applied to explore effects of time and of contraction level. Statistical significance was accepted as p<0.05. Knee extensor maximum voluntary contraction (MVC), jump power, force steadiness, and balance did not differ across the menstrual phases (all p>0.4). Firing rate of low threshold MU (10% MVC) was reduced during phases of high progesterone ({beta}=-0.82Hz, p<0.001), with no difference in MUPs analysed from 25% MVC contractions. MUPs were more complex during ovulation and mid luteal phase (p<0.03), with no change in neuromuscular junction transmission instability (p>0.3). Assessments of neuromuscular performance did not differ across the menstrual cycle. The suppression of low threshold MU firing rate during periods of increased progesterone may suggest a potential inhibitory effect and an alteration of recruitment strategy, however this had no discernible effect on performance. These findings highlight contraction level dependent modulation of VL MU function over the eumenorrheic cycle.

physiology↗

bioRxiv2023

Reduced motoneuron excitability and common synaptic inputs of the aged human vastus lateralis

Although muscle atrophy may partially account for age-related strength decline, it is further influenced by alterations of neural input to muscle. Persistent inward currents and the level of common synaptic inputs to motoneurons influence neuromuscular function. However, these have not yet been described in aged human quadriceps. High density surface electromyography (HDsEMG) signals were collected from the vastus lateralis of 15 young (mean{+/-}SD, 23 {+/-} 5 y) and 15 older (67 {+/-} 9 y) men during submaximal sustained and 20-s ramped contractions. HDsEMG signals were decomposed to identify individual motor unit discharges, from which delta F and intramuscular coherence were estimated. Older participants produced significantly lower knee extensor torque (p<0.001) and poorer force tracking ability (p<0.001) than young. Older participants also had lower delta F (p=0.001) and coherence estimates in the alpha frequency band (p<0.001) during ramp contractions when compared to young. Persistent inward currents and common synaptic inputs are lower in the vastus lateralis of older males when compared to young. These data highlight altered neural input to the clinically and functionally important quadriceps, further underpinning age-related loss of function which may occur independently of the loss of muscle mass. Key PointsO_LIThe age-related loss of muscle mass is exceeded by the loss of function, which is influenced by structural and functional alterations of the nervous system. C_LIO_LIMotoneuronal persistent inward currents and common synaptic inputs play an important role in the activation of motor units and subsequent force generation and control ability. C_LIO_LIHere we show reduced estimates of persistent inward currents and lower common synaptic inputs to older vastus lateralis, potentially contributing to observed lower strength and poorer force tracking. C_LIO_LIThese findings highlight decrements of the aged human motor system, accompanied by muscle atrophy in functionally relevant muscle groups, which should be considered in the application of interventions targeting aged human muscle. C_LI

physiology↗

bioRxiv2023

Variation in spatial dependencies across the cortical mantle discriminates the functional behaviour of primary and association cortex

Recent theories of cortical organisation maintain that important features of brain function emerge through the spatial arrangement of regions of cortex. For example, areas of association cortex are located in regions of cortex furthest from sensory and motor cortex. Association cortex is also interdigitated since adjacent regions can have relatively different patterns of functional connectivity. It is assumed that topographic properties such as distance between cortical regions constrain their functions. For example, large distances between association and sensory and motor systems may enable these areas of cortex to maintain differentiable neural patterns, while an interdigitated organisation may enable association cortex to contain many functional systems in a relatively compact space. We currently lack a formal understanding of how spatial organisation impacts brain function, limiting the ability to leverage cortical topography to facilitate better interpretations of a regions function. Here we use variograms, a quantification of spatial autocorrelation, to develop a cortex-wide profile of how functional similarity changes as a function of the distance between regions. We establish that function changes gradually within sensory and motor cortex as the distance between regions increases, while in association cortex function changes rapidly over shorter distances. Subsequent analysis suggests these differential classes of spatial dependency are related to variation in intracortical myelin between sensory motor and association cortex. Our study suggests primary and association cortex are differentiated by the degree to which function varies over space, emphasising the need to formally account for spatial properties when estimating a systems contribution to cognition and behaviour. Significance statementThe spatial arrangements of regions in the human brain are hypothesised to underpin important features of a brain regions function. Currently, however, we lack a formal understanding of how topography shapes brain function, limiting our ability to leverage topographical perspectives to inform better theories of brain function. Here we use a formal mathematical approach to establish that in regions of association cortex function varies across the cortex more rapidly than in sensory and motor cortex, a phenomenon linked to levels of intracortical myelin. This result highlights how topographical features distinguish between cortical regions with different functional profiles and provides a formal account of how spatial differences support different features of brain function.

neuroscience↗

bioRxiv2022

Mapping human social brain specialisation beyond the neuron using multimodal imaging in human infants

The specialised regional functionality of the mature human cortex partly emerges through experience-dependent specialisation during early development. Our existing understanding of this process is based on evidence from unitary imaging modalities and has thus focused on isolated changes in spatial or temporal precision of neural or haemodynamic activation alone, giving an incomplete picture of the process. We speculate that neural specialisation of function will be underpinned by better coordinated haemodynamic and metabolic changes in a broader orchestrated physiological response. Thus, we present a harmonised framework in which specialisation is indexed by the emergence of coupling between neuronal activity and vascular supply of oxygen and energy. Here, we combine simultaneous measures of coordinated neural activity (EEG), metabolic rate and oxygenated blood supply (broadband near-infrared spectroscopy) to measure emerging specialisation in the infant brain. In 4-to-7-month-old infants, we show that social processing is accompanied by spatially and temporally specific increases in coupled activation in the temporal-parietal junction, a core hub region of the adult social brain. During non-social processing coupled activation decreased in the same region, indicating specificity to social processing. Coupling was strongest with high frequency brain activity (beta and gamma), consistent with the greater energetic requirements and more localised action of high frequency brain activity. We conclude that functional specialisation of the brain is a coordinated activity across neural, haemodynamic, and metabolic changes, and our ability to measure these simultaneously opens new vistas in understanding how the brain is shaped by its environment.

developmental biology↗

bioRxiv2022

Training induced improvements in knee extensor force accuracy are associated with reduced vastus lateralis motor unit firing variability

BackgroundMuscle force output during sustained submaximal isometric contractions fluctuates around an average value and is known to be influenced by variation in motor unit (MU) firing rates. MU firing rate variability seemingly reduces following exercise training interventions, however, much less is known with respect to peripheral MU properties. We therefore investigated whether targeted force accuracy training could lead to improved muscle functional capacity and control, in addition to determining any alterations of individual MU features. MethodsTen healthy participants (7 females, 3 males, 27{+/-}6 years, 170{+/-}8 cm, 69{+/-}16kg) underwent a 4-week supervised, unilateral, force accuracy training intervention. The coefficient of variation for force (FORCECoV) and sinusoidal wave force tracking accuracy (FORCESinu) were determined at 25% maximal voluntary contraction (MVC) pre- and post-training. Intramuscular electromyography was utilised to record individual MU potentials from the vastus lateralis (VL) muscles at 25% MVC during sustained contractions, pre- and post-training. ResultsKnee extensor muscle strength remained unchanged following training, with no improvements in unilateral leg-balance. FORCECoV and FORCESinu significantly improved in only the trained knee extensors by ~13% (p=0.01) and ~30% (p<0.0001) respectively. MU firing rate variability significantly reduced in the trained VL by ~16% (n=8; p=0.001), with no further alterations to MU firing rate or neuromuscular junction transmission instability. ConclusionOur results suggest muscle force control and tracking accuracy is a trainable characteristic in the knee extensors, which is likely explained by the reduction in MU firing rate variability apparent in the trained limb only.

physiology↗

bioRxiv2021

Non-conventional serine protease activity of the CXC chemokine-cleaving streptococcal enzyme, SpyCEP

The Streptococcus pyogenes cell envelope protease (SpyCEP) is vital to streptococcal pathogenesis and disease progression. Despite its strong association with invasive disease, little is known about enzymatic function beyond the ELR+ CXC chemokine substrate range. As a serine protease, SpyCEP has a catalytic triad consisting of aspartate (D151), histidine (H279), and serine (S617) residues which are all thought to be mandatory for full activity. We utilised a range of SpyCEP constructs to investigate the protein domains and catalytic residues necessary for enzyme function. We designed a high-throughput mass spectrometry assay to measure CXCL8 cleavage and applied this for the first time to study the enzyme kinetics of SpyCEP. Results revealed a remarkably low Michaelis-Menton constant (KM) of 82 nM and a turnover of 1.65 molecules per second. We found that an N-terminally-truncated SpyCEP C-terminal construct containing just the catalytic dyad of H279 and S617 was capable of cleaving CXCL8 with a similar KM of 55 nM, albeit with a reduced substrate turnover of 2.7 molecules per hour, representing a 2,200- fold reduction in activity. We conclude that the SpyCEP C-terminus plays a key role in high affinity substrate recognition and binding, but that the N-terminus is required for full catalytic activity.

microbiology↗