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Roberts, M.

Publications and source records attributed to Roberts, M..

29 records · Page 2Linked to original sources

Towards modelling cold-water coral reef-scale crumbling: Including morphological variability in mechanical surrogate models

The structural complexity of cold-water corals is threatened by ocean acidification. Increased porosity and weakening of structurally critical parts of the reef framework may lead to rapid physical collapse on an ecosystem scale, reducing their potential for biodiversity support. We can use computational models to describe the mechanisms leading to reef-crumbling. How-ever, the implementation of such models into an efficient predictive tool that allows us to determine risk and timescales of reef collapse is missing. Here, we identified possible surrogate models to represent the branching architecture of the cold-water coral species Lophelia pertusa. For length scales greater than 13 cm, a continuum finite element mechanical approach can be used to analyse mechanical competence whereas at smaller length scales, mechanical surrogate models need to explicitly account for the statistical differences in the structure. We showed large morphological variations between L. pertusa colonies and branches, as well as dead and live skeletal structures, which need to be considered for the development of rapid monitoring tools for predicting risk of cold-water coral reefs crumbling. This will allow us to investigate timescales of changes, including the impact of exposure times to acidified waters on reef-crumbling.

bioengineering↗

Interrogating the Precancerous Evolution of Pathway Dysfunction in Lung Squamous Cell Carcinoma Using XTABLE

Lung squamous cell carcinoma (LUSC) is a type of lung cancer with a dismal prognosis that lacks adequate therapies and actionable targets. This disease is characterized by a sequence of low and high-grade preinvasive stages with increasing probability of malignant progression. Increasing our knowledge about the biology of these premalignant lesions (PMLs) is necessary to design new methods of early detection and prevention, and to identify the molecular processes that are key for malignant progression. To facilitate this research, we have designed XTABLE, an open-source application that integrates the most extensive transcriptomic databases of PMLs published so far. With this tool, users can stratify samples using multiple parameters and interrogate PML biology in multiple manners, such as two and multiple group comparisons, interrogation of genes of interests and transcriptional signatures. Using XTABLE, we have carried out a comparative study of the potential role of chromosomal instability scores as biomarkers of PML progression and mapped the onset of the most relevant LUSC pathways to the sequence of LUSC developmental stages. XTABLE will critically facilitate new research for the identification of early detection biomarkers and acquire a better understanding of the LUSC precancerous stages.

bioinformatics↗

Effects of High-Volume versus High-Load Resistance Training on Skeletal Muscle Growth and Molecular Adaptations

AimWe evaluated the effects of higher-load (HL) versus (lower-load) higher-volume (HV) resistance training on skeletal muscle hypertrophy, strength, and muscle-level molecular markers. MethodsTrained men (n=15, age: 23{+/-}3 y; training experience: 7{+/-}3 y) performed unilateral lower body training for 6 weeks (3x weekly), where single legs were assigned to HV and HL paradigms. Vastus lateralis (VL) biopsies were obtained prior to study initiation (PRE) as well as 3 days (POST) and 10 days following the last bout (POSTPR). Body composition and strength tests were performed at each testing session, and biochemical assays were performed on muscle tissue after study completion. Two-way within subjects repeated measures ANOVAs were performed on all dependent variables except tracer data, which was compared using dependent samples t-tests. ResultsA significant (p<0.05) interaction existed for unilateral leg extension 1RM (HV<HL at POST and POSTPR). Six-week integrated sarcoplasmic protein synthesis (iSarcoPS) rates were higher in the HV versus HL leg, while no difference between legs existed for integrated myofibrillar protein synthesis rates. Main time effects existed for unilateral leg press strength (PRE<POST and POSTPR), knee extensor peak torque (PRE and POST<POSTPR), dual-energy x-ray absorptiometry (DXA)-derived upper leg lean mass (PRE<POST and POSTPR), ultrasound-derived VL thickness (PRE and POSTPR<POST), sarcoplasmic protein concentrations (POST and POSTPR<PRE), and tropomyosin and troponin protein abundances (POST and POSTPR<PRE). ConclusionsWith the exception of differences in leg extensor strength and iSarcoPS between legs, our data suggest that short-term (6 weeks) HV and HL training elicit similar hypertrophic, strength, and molecular-level adaptations.

physiology↗

Exogenous attention generalizes perceptual learning in adults with amblyopia

Visual perceptual learning (VPL) is a behavioral manifestation of brain neuroplasticity. However, its practical effectiveness is limited because improvements are often specific to the trained conditions and require significant time and effort. It is critical to understand the conditions that promote learning and transfer. Covert endogenous (voluntary) and exogenous (involuntary) spatial attention help overcome VPL location specificity in neurotypical adults, but whether they also do so for people with atypical visual development is unknown. This is the first study to investigate the role of exogenous attention during VPL in adults with amblyopia, an ideal population given their asymmetrically developed, but highly plastic, visual cortex. Here we show that training on a discrimination task leads to improvements in foveal contrast sensitivity, acuity, and stereoacuity. Remarkably, exogenous attention helps generalize learning beyond trained spatial locations. Our findings reveal that attention can enhance the effectiveness of perceptual learning during rehabilitation of visual disorders.

neuroscience↗

Low immunogenicity of malaria pre-erythrocytic stages can be overcome by vaccination

Vaccine discovery and development critically depends on predictive assays, which prioritise protective antigens. Immunogenicity is considered one important criterion for progression of candidate vaccines to further clinical evaluation, including phase I/II trials. Here, we tested this assumption in an infection and vaccination model for malaria pre-erythrocytic stages. We engineered Plasmodium berghei parasites that harbour a well-characterised epitope for stimulation of CD8+ T cells either as an antigen in the circumsporozoite protein (CSP), the surface coat protein of extracellular sporozoites or in the upregulated in sporozoites 4 (UIS4), a major protein associated with the parasitophorous vacuole membrane (PVM) that surrounds the intracellular exo-erythrocytic forms (EEF). We show that the antigen origin results in profound differences in immunogenicity with a sporozoite antigen eliciting robust and superior antigen-specific CD8+ T cell responses, whilst an EEF antigen evokes poor responses. However, despite their contrasting immunogenic properties, both sporozoite and EEF antigens gain access to antigen presentation pathways in hepatocytes, as recognition and targeting by vaccine-induced, antigen-specific effector CD8+ T cells results in high levels of protection when targeting both antigens. Our study is the first demonstration that poor immunogenicity of EEF antigens does not preclude their susceptibility to antigen-specific CD8+ T cell killing. Our findings that antigen immunogenicity is an inadequate predictor of vaccine susceptibility have wide-ranging implications on antigen prioritisation for the design and testing of next-generation pre-erythrocytic malaria vaccines.

immunology↗

Empirically Constrained Network Models for Contrast-dependent Modulation of Gamma Rhythm in V1

Here we present experimentally constrained computational models of gamma rhythm and use these to investigate gamma oscillation instability. To this end, we extracted empirical constraints for PING (Pyramidal Interneuron Network Gamma) models from monkey single-unit and LFP responses recorded during contrast variation. These constraints implied weak rather than strong PING, connectivity between excitatory (E) and inhibitory (I) cells within specific bounds, and input strength variations that modulated E but not I cells. Constrained models showed valid behaviours, including gamma frequency increases with contrast and power saturation or decay at high contrasts. The route to gamma instability involved increased heterogeneity of E cells with increasing input triggering a breakdown of I cell pacemaker function. We illustrate the models capacity to resolve disputes in the literature. Our work is relevant for the range of cognitive operations to which gamma oscillations contribute and could serve as a basis for future, more complex models.

neuroscience↗

Muscle fiber hypertrophy in response to 6 weeks of high-volume resistance training in trained young men is largely attributed to sarcoplasmic hypertrophy

Cellular adaptations that occur during skeletal muscle hypertrophy in response to high-volume resistance training are not well-characterized. Therefore, we sought to explore how actin, myosin, sarcoplasmic protein, mitochondrial, and glycogen concentrations were altered in individuals that exhibited mean skeletal muscle fiber cross-sectional area (fCSA) hypertrophy following 6 weeks of high-volume resistance training. Thirty-one previously resistance-trained, college-aged males (mean {+/-} standard deviation: 21{+/-}2 years, 5{+/-}3 training years) had vastus lateralis (VL) muscle biopsies obtained prior to training (PRE), at week 3 (W3), and at week 6 (W6). Muscle tissue from 15 subjects exhibiting PRE to W6 VL mean fCSA increases ranging from 320-1600 m2 was further interrogated using various biochemical and histological assays as well as proteomic analysis. Seven of these individuals donated a VL biopsy after refraining from training 8 days following the last training session (W7) to determine how deloading affected biomarkers. The 15 fCSA hypertrophic responders experienced a +23% increase in mean fCSA from PRE to W6 (p<0.001) and, while muscle glycogen concentrations remained unaltered, citrate synthase activity levels decreased by 24% (p<0.001) suggesting mitochondrial volume decreased. Interestingly, both myosin and actin concentrations decreased ~30% from PRE to W6 (p<0.05). Phalloidin-actin staining similarly revealed actin concentrations per fiber decreased from PRE to W6. Proteomic analysis of the sarcoplasmic fraction from PRE to W6 indicated 40 proteins were up-regulated (p<0.05), KEGG analysis indicated that the glycolysis/gluconeogenesis pathway was upregulated (FDR sig. <0.001), and DAVID indicated that the following functionally-annotated pathways were upregulated (FDR value <0.05): a) glycolysis (8 proteins), b) acetylation (23 proteins), c) gluconeogenesis (5 proteins) and d) cytoplasm (20 proteins). At W7, sarcoplasmic protein concentrations remained higher than PRE (+66%, p<0.05), and both actin and myosin concentrations remained lower than PRE (~-50%, p<0.05). These data suggest that short-term high-volume resistance training may: a) reduce muscle fiber actin and myosin protein concentrations in spite of increasing fCSA, and b) promote sarcoplasmic expansion coincident with a coordinated up-regulation of sarcoplasmic proteins involved in glycolysis and other metabolic processes related to ATP generation. Interestingly, these effects seem to persist up to 8 days following training.

molecular biology↗

Experience-related alterations in white matter structure and gene expression in adult rats

White matter (WM) plasticity during adulthood is a recently described phenomenon by which experience can shape brain structure. It has been observed in humans using diffusion tensor imaging (DTI). However, it remains unclear which mechanisms drive or underlie WM plasticity in adulthood. Here, we combined DTI and mRNA expression analysis and examined the effects of somatosensory experience in adult rats. Somatosensory experience resulted in differences in WM and grey matter structure. C-FOS mRNA expression, a marker of cortical activity, in the barrel cortex correlated with the structural WM measures, suggesting that WM plasticity is activity-dependent. Analysis of myelin-related genes revealed higher myelin basic protein expression in WM, while genome-wide RNA sequencing analysis identified 134 differentially-expressed genes regulating proteins involved in functions related to cell proliferation and differentiation, neuronal activity modulation and regulation of myelination. In conclusion, the macroscale measures of WM differences identified in response to somatosensory experience are supported by molecular evidence, which strongly suggest myelination as, at least, one of the underlying mechanisms.

neuroscience↗

A TauP301L mouse model of dementia; development of pathology, synaptic transmission, microglial response and cognition throughout life

BackgroundLate stage Alzheimers disease and other dementias are associated with neurofibrillary tangles and neurodegeneration. Here we describe a mouse (TauD35) carrying human Tau with the P301L mutation that results in Tau hyperphosphorylation and tangles. Previously we have compared gene expression in TauD35 mice to mice which develop plaques but no tangles. A similar comparison of other pathological features throughout disease progression is made here between amyloid{beta} and Tau mice described in Parts I and II of this study.\n\nMethodsIn vitro CA1 patch clamp and field recordings were used to investigate synaptic transmission and plasticity. Plaque load and microglia were investigated with immunohistochemistry. Cognition, locomotor activity and anxiety-related behaviours were assessed with a forced-alternation T-maze, open field and light/dark box.\n\nResultsTransgene copy number in TauD35 mice fell into two groups (HighTAU and LowTAU), allowing assessment of dose-dependent effects of overexpression and resulting in tangle load increasing 100-fold for a 2-fold change in protein levels. Tangles were first detected at 8 (HighTAU) or 13 months (LowTAU) but the effects on synaptic transmission and plasticity and behaviour were subtle. However severe neurodegeneration occurred in HighTAU mice at around 17 months preceded by considerable proliferation but little additional activation of microglia. Proliferation only started as neurodegeneration began at 13 months. Similarly to HighTau mice at 13 months of age, LowTAU mice at 24 months of age showed a comparable tangle load and microglial proliferation. However, LowTAU mice showed no neurodegeneration at this stage and considerable microglial activation, stressing the dependence of these effects on overexpression and/or age.\n\nConclusionsComparison of the effects of amyloid{beta} and plaques without tangles in a model of preclinical Alzheimers disease to the effects of tangles without amyloid{beta} plaques in the late stage model described here may clarify the progressive stages of Alzheimers disease. While Tau hyperphosphorylation and neurofibrillary tangles are eventually sufficient to cause severe neurodegeneration, initial effects on synaptic transmission and the immune response are subtle. In contrast while even with a heavy plaque load little if any neurodegeneration occurs, considerable effects on synaptic transmission and the immune system result, even before plaques are detectable.

neuroscience↗

Quantitative analysis of synaptic pathology and neuroinflammation: an initial study in a female rhesus monkey model of the “synaptic” phase of Alzheimer’s disease

BackgroundSoluble oligomers of the A{beta} peptide (A{beta}Os) are toxins that target and disrupt synapses. Generation of A{beta}Os has been recently recognized as a probable initiating event in Alzheimers disease (AD), leading to cognitive impairment. There is a translational gap in AD studies, with promising drugs developed based on work in rodent models failing in AD patients in clinical trials. Additionally, although women have a two-fold greater lifetime risk of developing AD compared to men, females have not been a focus of preclinical studies. Thus, we sought to develop a model of A{beta}O toxicity in female rhesus monkeys, to take advantage of the more highly differentiated cortical structure in this species as well as the similarities in the endocrine system between rhesus monkeys and humans.\n\nMethodsRepeated intracerebroventricular (i.c.v) injections of A{beta}Os were performed in adult female rhesus monkeys. Controls were unoperated aged matched monkeys. High-resolution confocal microscopy and morphometric analysis of Alexa 568 (A568) filled neurons were used to evaluate synaptic, neuronal, and glial markers in the dorsolateral prefrontal cortex (dlPFC) and hippocampus after A{beta}O injections. Cerebrospinal fluid (CSF) and brain tissue were also collected and analyzed for biomarkers of AD pathology, including: phosphorylated Tau protein (pTau), total Tau, A{beta}1-42, A{beta}1-40 and TNF- levels.\n\nResultsHere, we report that A{beta}O injection into the lateral ventricle of the brain induces loss of 37% of thin spines in targeted dlPFC neurons, an area highly vulnerable in AD and aging. Further, A{beta}Os associate with the synaptic marker PSD95, inducing loss of more than 60% of local excitatory synapses. A{beta}Os induce a robust neuroinflammatory response in the hippocampus, far from the injection site, with numerous activated ameboid microglia and TNF- release. Finally, A{beta}Os increased CSF levels of A{beta}1-42, pTau Ser396 and pTau Ser199, but not A{beta}1-40 or total Tau.\n\nConclusionsThese initial findings from detailed quantitative analysis of effects of A{beta}O administration on synapses in a female nonhuman primate model are a very promising step toward understanding the mechanism of early AD pathogenesis in the primate brain, and may help develop an effective disease-modifying therapy of high relevance to womens health.

neuroscience↗

Burst Activation Of Dopamine Neurons Produces Prolonged Post-Burst Availability Of Actively Released Dopamine

Both phasic and tonic modes of neurotransmission are implicated in critical functions assigned to dopamine. In learning, for example, sub-second phasic responses of ventral tegmental area (VTA) dopamine neurons to salient events serve as teaching signals, but learning is also interrupted by dopamine antagonists administered minutes after training. Our findings bridge the multiple timescales of dopamine neurotransmission by demonstrating that burst stimulation of VTA dopamine neurons produces a prolonged post-burst increase (> 20 min) of extracellular dopamine in nucleus accumbens and prefrontal cortex. This elevation is not due to spillover from the stimulation surge but depends on impulse flow-mediated dopamine release. We identified Rho-mediated internalization of dopamine transporter as a mechanism responsible for prolonged availability of actively released dopamine. These results demonstrate that phasic and tonic dopamine neurotransmission can be a continuum and may explain why both modes of signaling are critical for motivational and cognitive functions associated with dopamine.

neuroscience↗