Biology subjects

Kessler, K.

Publications and source records attributed to Kessler, K..

13 recordsLinked to original sources

bioRxiv2026

Cooperativity through Allee Effects drives growth of diffuse midline gliomas impacting the optimal scheduling of therapeutic interventions

Diffuse midline gliomas are a group of tumours for which no effective therapies exist. These tumours have substantial intratumoural heterogeneity and harbour beneficial subclonal interactions. Therapeutic failure due to resistance is a major concern in these tumours. We demonstrate how distinct subpopulations derived from the same tumour can interact with one another to alleviate the impacts of therapeutic intervention. This is achieved through the establishment of a mathematical extension to the Lotka-Volterra competition model, where interactions perturbing the Allee effect were demonstrated to exist. These interactions had substantial downstream consequences as they were determined to be perturbed by therapeutic interventions and strikingly, when simulating a two-drug paradigm, the interactions were demonstrated to substantially later the outcomes of treatment scheduling.

cancer biology↗

bioRxiv2025

Epigenetic and Transcriptomic Alterations Precede Amyloidosis in the Hippocampus of the Alzheimer's Disease AppNL-G-F Knock in Mouse Model

Detecting and understanding the early stages of Alzheimers disease (AD) is essential for uncovering initial mechanisms of neuropathology and devising effective interventions. In this study, we leveraged the humanized AppNL-G-F mouse which exhibits early-onset amyloid pathology with a predictable timeline, to investigate molecular changes in the hippocampus and blood before the onset of severe neuropathology and independent of aging. Employing a multi-omics approach, we identified alterations in chromatin accessibility, gene expression, and DNA methylation associated with early amyloidosis. Chromatin accessibility changes were prominent in excitatory neurons during early pathology, with a later shift to inhibitory neurons, potentially reflecting compensatory mechanisms to mitigate excitatory neuron dysregulation. Despite broadly comparable hippocampal cell composition, transcriptomic comparisons between wild-type and AppNL-G-F mice revealed major gene expression differences, particularly in pathways related to mitochondrial function and protein biosynthesis, preceding severe amyloid plaque deposition. In later stages, upregulation of immune and neuroinflammatory pathways was observed, aligning with established neuroinflammatory processes in AD. Additionally, we identified extensive DNA methylation differences in both the blood and hippocampus of AppNL-G-Fmice during early and late stages of pathology. Many differentially methylated regions in the blood, even at early pathology stages, were associated with cis-regulatory elements in the brain and were located near differentially expressed genes in the hippocampus. These regions were enriched in pathways associated with brain function, including neuron development and synaptic processes, highlighting a connection between blood methylation patterns and brain activity. This finding suggests the potential use of blood DNA methylation as a biomarker for the early detection of amyloidosis. Notably, we identified five candidate biomarker genes, including Rbfox1 and Camta1, with epigenetic dysregulation detectable in both the brain and blood prior to severe amyloid accumulation. Our study, leveraging a unique AD mouse model and a multi-omics approach, highlights epigenetic signatures of AD before the onset of clinical symptoms, providing a foundation for future research into early diagnosis and therapeutic strategies, as well as potential blood biomarkers.

molecular biology↗

bioRxiv2024

The Neural Oscillatory Basis of Perspective-Taking in Autistic and Non-Autistic Adolescents using MEG

Taking anothers perspective is a high-level mental skill underlying many aspects of social cognition. Perspective-taking is usually an embodied egocentric process whereby people mentally rotate themselves away from their physical location into the others orientation. This is accompanied by increased theta-band (3-7 Hz) brain oscillations within a widespread fronto-parietal cortical network including the temporoparietal junction. Individuals with autism spectrum disorder (ASD) have been reported to experience challenges with high-level perspective-taking, particularly when adopting embodied strategies. To investigate the potential neurophysiological basis of these autism-related individual differences, we used magnetoencephalography in combination with a well-replicated perspective-taking paradigm in a group of 18 autistic and 17 age-matched non-autistic adolescents. Findings revealed that increasing the angle between self and other perspective resulted in prolonged reaction times for the autistic group during perspective-taking. This was accompanied by reduced theta power across a wide network of regions typically active during social cognitive tasks. On the other hand, the autistic group showed greater alpha power decreases in visual cortex compared with the non-autistic group across all perspective-taking conditions. These divergent theta and alpha power effects, coupled with steeper response time slopes, suggest that autistic individuals may rely more on alternative cognitive strategies, such as mental object rotation, rather than an egocentric embodied approach. Finally, no group differences were found when participants were asked to track, rather than take, anothers viewpoint, suggesting that autism-related individual differences are specific to high-level perspective-taking.

neuroscience↗

bioRxiv2021

Loss of the H4 lysine methyltransferase KMT5B drives tumorigenic phenotypes by depleting H3K27me3 at loci otherwise retained in H3K27M mutant DIPG cells

DIPG are characterised by histone H3K27M mutations, resulting in global loss of the repressive mark H3K27me3, although certain key loci are retained. We recently identified subclonal loss-of-function mutations in the H4 lysine methyltransferase KMT5B to be associated with enhanced invasion/migration, but the mechanism by which this occurred was unclear. Here we use integrated ChIP-seq, ATAC-seq and RNA-seq on patient-derived, subclonal and CRISPR-Cas9-KD DIPG cells to show that loss of KMT5B/C causes depletion of these retained H3K27me3 loci via changes in chromatin accessibility, causing a raft of transcriptional changes which promote tumorigenesis. De-repression occurred at bivalent loci marked by H3K4me3, driving increased transcriptional heterogeneity and elevated gene expression associated with increased invasion, abrogated DNA repair and mesenchymal transition, along with a markedly altered secretome. These data suggest a previously unrecognised trans-histone (H4/H3) interaction in DIPG cells with a potentially profound effect on their diffusely infiltrating phenotype.

cancer biology↗

bioRxiv2021

Quantification of spatial subclonal interactions enhancing the invasive phenotype of paediatric glioma

Intra-tumour heterogeneity is an intrinsic property of all cancers. In some cases, such variation can be maintained by interactions between tumour subclones with distinct molecular and phenotypic characteristics. In paediatric gliomas, interactions can take the form of enhanced invasive phenotype, a hallmark of these malignancies. However, subclonal interactions are hard to quantify and difficult to distinguish from spatial confounding factors and experimental bias. Here we combine spatial computational modelling of cellular interactions and invasion, with co-evolution experiments of clonally disassembled primary glioma lines derived at autopsy. We design a Bayesian inference framework to quantify spatial subclonal interactions between molecular and phenotypically distinct lineages with different patterns of invasion. We show how this approach could discriminate genuine subclonal interactions where one clone enhanced the invasive phenotype of another, from apparent interactions that were only due to the complex dynamics of subclones growing in space. This study provides a new approach for the identification and quantification of spatial subclonal interactions in cancer.

cancer biology↗

bioRxiv2021

Event-related and oscillatory signatures of response inhibition: A magnetoencephalography study with subclinical high and low impulsivity adults

Inhibition, the ability to withhold a response or to stop an initiated response, is a necessary cognitive function that can be vulnerable to an impairment. High levels of impulsivity have been shown to impact response inhibition and/or cognitive task performance. The present study investigated the spectral and spatio-temporal dynamics of response inhibition, during a combined go/no-go/stop-signal task, using magnetoencephalography (MEG) in a healthy undergraduate student population. Participants were divided by their level of impulsivity, as assessed by self-report measures, to explore potential differences between high (n=17) and low (n=17) impulsivity groups. Results showed that individuals scoring high on impulsivity failed significantly more NOGO and STOP trials than those scoring low, but no significant differences were found between stop-signal reaction times. During NOGO and STOP conditions, high impulsivity individuals showed significantly smaller M1 components in posterior regions, which could suggest an attentional processing deficit. During NOGO trials, the M2 component was found to be reduced in individuals scoring high, possibly reflecting less pre-motor inhibition efficiency, whereas in STOP trials, the network involved in the stopping process was engaged later in high impulsivity individuals. The high impulsivity group also engaged frontal networks more during the STOP-M3 component only, possibly as a late compensatory process. The lack of response time differences on STOP trials could indicate that compensation was effective to some degree (at the expense of higher error rates). Decreased frontal delta and theta band power was observed in high impulsivity individuals, suggesting a possible deficit in frontal pathways involved in motor suppression, however, unexpectedly, increased delta and theta band power in central and posterior sensors was also observed, which could be indicative of an increased effort to compensate for frontal deficits. Individuals scoring highly also showed decreased alpha power in frontal sensors, suggesting decreased inhibitory processing, along with reduced alpha suppression in posterior regions, reflecting reduced cue processing. These results provide evidence for how personality traits, such as impulsivity, relate to differences in the neural correlates of response inhibition.

neuroscience↗

bioRxiv2020

Drug screening linked to molecular profiling identifies novel dependencies in patient-derived primary cultures of paediatric high grade glioma and DIPG

Paediatric high grade glioma and diffuse midline glioma (including DIPG) are comprised of multiple biological and clinical subgroups, the majority of which urgently require novel therapies. Patient-derived in vitro primary cell cultures represent potentially useful tools for mechanistic and preclinical investigation based upon their retention of key features of tumour subgroups under experimental conditions amenable to high-throughput approaches. We present 17 novel primary cultures derived from patients in London, Dublin and Belfast, and together with cultures established or shared from Barcelona, Brisbane, Rome and Stanford, assembled a panel of 52 models under 2D (laminin matrix) and/or 3D (neurospheres) conditions, fully credentialed by phenotypic and molecular comparison to the original tumour sample (methylation BeadArray, panel/exome sequencing, RNAseq). In screening a subset of these against a panel of ~400 approved chemotherapeutics and small molecules, we identified specific dependencies associated with tumour subgroups and/or specific molecular markers. These included MYCN-amplified cells and ATM/DNA-PK inhibitors, and DIPGs with PPM1D activating truncating mutations and inhibitors of MDM2 or PARP1. Specific mutations in PDGFRA were found to confer sensitivity to a range of RTK inhibitors, though not all such mutations conferred sensitivity to targeted agents. Notably, dual PDGFRA/FGFR and downstream pathway MEK inhibitors showed profound effects against both PDGFRA-sensitising mutant and FGFR1-dependent non-brainstem pHGG and DIPG. In total, 85% cells were found to have at least one drug screening hit in short term assays linked to the underlying biology of the patients tumour, providing a rational approach for individualised clinical translation.

cancer biology↗

bioRxiv2019

The right temporoparietal junction is causally associated with embodied perspective taking

Several theories exist pertaining to the role of the right temporoparietal junction (rTPJ) in social cognition. A prominent theory claims the rTPJ is especially associated with embodied processes. In the present study we use high-definition transcranial direct current stimulation (HD-tDCS) to provide evidence that the rTPJ is causally associated with the embodied processes underpinning perspective taking. Eighty-eight young human adults were stratified to receive either rTPJ or dorsomedial prefrontal (dmPFC) anodal HD-tDCS in a sham-controlled, double-blind, repeated-measures design. Perspective tracking (line-of-sight) and perspective taking (embodied rotation) were assessed using a visuo-spatial perspective taking (VPT) task that required understanding what another person could see or how they see it, respectively. Embodied processing was manipulated by positioning the participant in a manner congruent or incongruent with the orientation of an avatar on the screen. As perspective taking, but not perspective tracking, is influenced by bodily posture, this allows the investigation of the specific causal role for the rTPJ in embodied processing. Crucially, anodal stimulation to the rTPJ increased the effect of bodily posture during perspective taking, whereas no such effects were identified during perspective tracking, thereby providing evidence for a causal role for the rTPJ in the embodied component of perspective taking. Stimulation to the dmPFC had no effect on perspective tracking or taking. Therefore, the present study provides support for theories postulating that the rTPJ is causally involved in embodied cognitive processing relevant to social functioning.\n\nSignificance StatementThe ability to understand anothers perspective is a fundamental component of social functioning. Adopting another perspective is thought to involve both embodied and non-embodied processes. The present study used high-definition transcranial direct current stimulation (HD-tDCS) and provided causal evidence that the right temporoparietal junction (rTPJ) is involved specifically in the embodied component of perspective taking. Specifically, HD-tDCS to the rTPJ, but not another hub of the social brain (dmPFC), increased the effect of body posture during perspective taking, but not tracking. This is the first causal evidence that HD-tDCS can modulate social embodied processing in a site-specific and task-specific manner.

neuroscience↗

bioRxiv2018

Flexible allocation of attention in time or space across the life span: Theta and alpha oscillatory signatures of age-related decline and compensation as revealed by MEG

In our recent behavioural research (Callaghan et al., 2017), we reported age-related changes in the costs of switching between from a temporal (rapid serial visual presentation) to a spatial (visual search) attention task. Using magnetoencephalography, we have now compared the neural signatures of attention refocusing between three age groups (19-30, 40-49 and 60+ years) and found differences in task-related modulation and cortical localisation of alpha and theta oscillations. Efficient, faster switching between the temporal and spatial attention tasks in the youngest group compared to both older groups was reflected in parietal theta effects that were significantly reduced in the older groups. Residual parietal theta activity in older individuals was, however, beneficial to attentional switching, and could reflect the preservation of attention mechanisms. Difficulties in refocusing attention in the older and middle-aged adults (slowed response times) were accompanied by reduced theta power modulation in occipital and cerebellar regions. In addition to this posterior theta deficit, older and middle-aged adults presented with increased recruitment of frontal (both groups) and temporal (older group) areas. Theta oscillations therefore demonstrated a posterior to anterior processing shift, which may reflect the engagement of alternative strategies in older- and middle-age, such as top-down attentional control in an attempt to compensate for posterior processing deficits. Additional frontal theta recruitment indeed appeared to be beneficial for faster performance, as reflected by correlational analysis. Temporal theta (in older-age), however, did not correlate with performance, but could reflect strategies unrelated to speeded performance (e.g. silent vocalisation to maintain task goals). Alpha oscillations did not significantly correlate with task performance, possibly reflecting decreased neural precision or de-differentiation, but require further investigation.

neuroscience↗

bioRxiv2018

Dysregulated Oscillatory Connectivity in the Visual System in Autism Spectrum Disorder

Autism Spectrum Disorder is increasingly associated with atypical perceptual and sensory symptoms. Here we explore the hypothesis that aberrant sensory processing in Autism Spectrum Disorder could be linked to atypical intra- (local) and inter-regional (global) brain connectivity. To elucidate oscillatory dynamics and connectivity in the visual domain we used magnetoencephalography and a simple visual grating paradigm with a group of 18 adolescent autistic participants and 18 typically developing controls. Both groups showed similar increases in gamma (40-80Hz) and decreases in alpha (8-13Hz) frequency power in occipital cortex. However, systematic group differences emerged when analysing intra- and inter-regional connectivity in detail. Firstly, directed connectivity was estimated using non-parametric Granger causality between visual areas V1 and V4. Feedforward V1-to-V4 connectivity, mediated by gamma oscillations, was equivalent between Autism Spectrum Disorder and control groups, but importantly, feedback V4-to-V1 connectivity, mediated by alpha (8-13Hz) oscillations, was significantly reduced in the Autism Spectrum Disorder group. This reduction was positively correlated with autistic quotient scores, consistent with an atypical visual hierarchy in autism, characterised by reduced top-down modulation of visual input via alpha-band oscillations. Secondly, at the local level in V1, coupling of alpha-phase to gamma amplitude (alpha-gamma phase amplitude coupling, PAC) was reduced in the Autism Spectrum Disorder group. This implies dysregulated local visual processing, with gamma oscillations decoupled from patterns of wider alpha-band phase synchrony (i.e. reduced PAC), possibly due to an excitation-inhibition imbalance. More generally, these results are in agreement with predictive coding accounts of neurotypical perception and indicate that visual processes in autism are less modulated by contextual feedback information.

neuroscience↗

bioRxiv2017

Oscillatory Networks of High-Level Mental Alignment: A Perspective-Taking MEG Study

Mentally imagining anothers perspective is a high-level social process, reliant on manipulating internal representations of the self in an embodied manner. Recently Wang et al., (1) showed that theta-band (3-7Hz) brain oscillations within the right temporo-parietal junction (rTPJ) and brain regions coding for motor/body schema contribute to the process of perspective-taking. Using a task requiring participants to engage in embodied perspective-taking, we set out to unravel the extended functional brain network and its connections in detail. We found that increasing the angle of disparity between self and other perspective was accompanied by longer reaction times and increases in theta power within rTPJ, right lateral pre-frontal cortex (PFC) and right anterior cingulate cortex (ACC). Using nonparametric Granger-causality, we showed that during later stages of perspective-taking, the lateral PFC and ACC exert top-down influences over rTPJ, indicative of executive control processes required for managing conflicts between self and other perspectives. Finally, we quantified patterns of whole-brain phase coupling (imaginary coherence) in relation to rTPJ during high-level perspective taking. Results suggest that rTPJ increases its theta-band phase synchrony with brain regions involved in mentalizing and regions coding for motor/body schema; whilst decreasing its synchrony to visual regions. Implications for neurocognitive models are discussed, and it is proposed that rTPJ acts as a hub to route bottom-up visual information to internal representations of the self during perspective-taking, co-ordinated by theta-band oscillations. The self is then projected onto the others perspective via embodied motor/body schema transformations, regulated by top-down cingulo-frontal activity.\n\nSignificance StatementHigh-level social processing, such as the ability to imagine anothers visuospatial experience of the world (perspective taking), is a core part of what makes us human. Building on a substantial body of converging previous evidence, our study reveals how concerted activity across the cortex in low frequencies (theta: 3-7 Hz) implements this crucial human process. We found that oscillatory power and connectivity (imaginary coherence, nonparametric Granger causality) at theta frequency linked functional sub-networks of executive control, mentalizing, and sensorimotor/body schema via a main hub located in the right temporo-parietal junction (rTPJ). Our findings inform neurocognitive models of social cognition by describing the co-ordinated changes in brain network connectivity, mediated by theta oscillations, during perspective-taking.

neuroscience↗

bioRxiv2017

The Detection of Phase Amplitude Coupling During Sensory Processing

1.There is increasing interest in understanding how the phase and amplitude of distinct neural oscillations might interact to support dynamic communication within the brain. In particular, previous work has demonstrated a coupling between the phase of low frequency oscillations and the amplitude (or power) of high frequency oscillations during certain tasks, termed phase amplitude coupling (PAC). For instance, during visual processing in humans, PAC has been reliably observed between ongoing alpha (8-13Hz) and gamma-band (>40Hz) activity. However, the application of PAC metrics to electrophysiological data can be challenging due to numerous methodological issues and lack of coherent approaches within the field. Therefore, in this article we outline the various analysis steps involved in detecting PAC, using an openly available MEG dataset from 16 participants performing an interactive visual task. Firstly, we localised gamma and alpha-band power using the Fieldtrip toolbox, and extracted time courses from area V1, defined using a multimodal parcellation scheme. These V1 responses were analysed for changes in alpha-gamma PAC, using four common algorithms. Results showed an increase in gamma (40-100Hz) - alpha (7-13Hz) PAC in response to the visual grating stimulus, though specific patterns of coupling were somewhat dependent upon the algorithm employed. Additionally, post-hoc analyses showed that these results were not driven by the presence of non-sinusoidal oscillations, and that trial length was sufficient to obtain reliable PAC estimates. Finally, throughout the article, methodological issues and practical guidelines for ongoing PAC research will be discussed.

neuroscience↗

bioRxiv2016

THETA-Rhythm makes the world go round: Dissociative effects of TMS theta vs alpha entrainment of right pTPJ on embodied perspective transformations

Introduction Introduction Materials and Methods Results and Discussion References Being able to imagine another persons experience and perspective of the world is a crucial human social ability (Call & Tomasello, 1999) and recent reports suggest that humans \"embody\" anothers viewpoint by mentally rotating their own body representation into the others orientation (Kessler, Cao, OShea, & Wang, 2014; Kessler & Rutherford, 2010; Kessler & Thomson, 2010; Surtees, Apperly, & Samson, 2013). Using Magnetoencephalography (MEG) our group recently reported in Cortex that brain oscillations at theta frequency (3-7 Hz), originating from the right posterior temporo-parietal-junction (pTPJ) reflected cognitive as well as embod ...

neuroscience↗