Biology subjects

Engel, T.

Publications and source records attributed to Engel, T..

16 recordsLinked to original sources

bioRxiv2026

P2X7 receptor antagonism potentiates seizure-suppressive effects of anti-seizure medications in human resected epileptic brain tissue

Resistance to anti-seizure medications (ASMs) remains a major clinical challenge in the management of epilepsy. Neuroinflammation has been implicated as a contributing mechanism and, consistent with this, antagonists of the ATP-gated P2X7 receptor (P2X7R) have been shown to enhance ASM efficacy in animal models. It remains unclear, however, if P2X7R antagonism is effective in human models of drug-resistant epilepsy. Here, we assessed the seizure-suppressive potential of the P2X7R antagonists AFC-5128 and JNJ-47965567 using electrophysiological recordings in acute resected brain slices from patients with epilepsy using artificial cerebrospinal fluid containing low Mg2+ and high K+ to evoked seizure-like events. P2X7R antagonists alone did not suppress seizure-like activity. When co-administered, however, P2X7R antagonists significantly enhanced the anti-seizure efficacy of carbamazepine and lorazepam. Notably, P2X7R antagonist treatment lowered Interleukin-1{beta} levels, and betaine, a drug targeting Interleukin-1{beta} release, mimicked the effects of P2X7R antagonists when combined with carbamazepine. Finally, mice with microglia-specific P2X7R depletion showed improved responsiveness to carbamazepine, suggesting P2X7R-mediated effects are partially mediated via their functions in microglia. These findings suggest that P2X7R-based therapies may represent an effective add-on approach for treating drug-resistant seizures associated with neuroinflammation.

neuroscience↗

bioRxiv2025

Shared and distinct microRNA profiles between HT22, N2A and SH-SY5Y cell lines and primary mouse hippocampal neurons

MicroRNAs (miRNA) are small non-coding RNAs that are key negative regulators of gene expression. Their roles include shaping the gene expression landscape during and after brain development by defining and maintaining levels of proteins that generate the distinct morphological and functional properties of neurons and other brain cell types. HT22, N2A, and SH-SY5Y are common immortalized neuronal cell lines that offer simple, less expensive, and time-saving options for in vitro modelling to evaluate miRNA functions. The extent to which these lines reflect primary neurons remains, however, unclear. Here, we benchmarked the miRNA profiles of cultured mouse hippocampal neurons against Argonaute-loaded miRNAs in the adult mouse hippocampus and miRNA data from the hippocampus of patients with drug-resistant temporal lobe epilepsy. We then compared the miRNA expression landscape in HT22, N2A and SH-SY5Y against mouse hippocampal primary cell cultures. We profiled over 700 miRNAs across the lines and detected 310 miRNAs in all four cell types. This included detection of neuron-enriched miRNAs such as miR-124 and miR-128, although the cell lines typically displayed lower levels of these than in primary neurons and reference adult hippocampal tissue. The miRNA profile in the HT22 cell line showed the highest correlation to the mouse primary neuronal cultures. Together, this study provides a dataset on basal miRNA expression across commonly used cell lines for neuroscience research and evidence for both conserved and distinct profiles that should be used to inform decisions on cell lines for modelling brain and miRNA research.

neuroscience↗

bioRxiv2024

Changes in wing morphology rather than wingbeat kinematics enabled evolutionary miniaturization of hoverflies

Due to physical scaling laws, size greatly affects animal locomotor ability and performance. Whether morphological and kinematic traits always jointly respond to size variation is however poorly known. Here, we examine the relative importance of morphological and kinematic changes in mitigating the consequence of size reduction on aerodynamic force production for weight support in flying insects, focusing on hovering flight of hoverflies (Syrphidae). We compared the morphology of 28 hoverfly species, and the flight biomechanics and aerodynamics of eight species with body masses ranging from 5 to 100 mg. Our study reveals no significant effect of body mass on wingbeat kinematics among species, suggesting that morphological rather than kinematic changes may compensate for the reduction in weight support associated with an isometric reduction in wing size. Computational Fluid Dynamics simulations confirmed that adaptations in wing morphology drive the ability of small hoverfly species to generate weight support, although variations in wingbeat kinematics between species cannot be completely neglected. We specifically show that smaller hoverflies have evolved relatively larger wings, and aerodynamically more effective wing shapes, to mitigate the reduction in aerodynamic weight support with isometric size reduction. Altogether, these results suggest that hoverfly flight underpins highly specialised wingbeat kinematics, which have been largely conserved throughout evolution; instead, evolutionary adaptations in wing morphology enabled flight of small hoverflies.

evolutionary biology↗

bioRxiv2023

Disentangling non-random structure from random placement when estimating β-diversity through space or time

There is considerable interest in understanding patterns of {beta}-diversity that measure the amount of change in species composition through space or time. Most hypotheses for {beta}-diversity evoke nonrandom processes that generate spatial and temporal within species aggregation; however, {beta}-diversity can also be driven by random sampling processes. Here, we describe a framework based on rarefaction curves that quantifies the non-random contribution of species compositional differences across samples to {beta}-diversity. We isolate the effect of within-species spatial or temporal aggregation on beta-diversity using a coverage standardized metric of {beta}-diversity ({beta}C). We demonstrate the utility of our framework using simulations and an empirical case study examining variation in avian species composition through space and time in engineered versus natural riparian areas. The primary strengths of our approach are that it provides an intuitive visual null model for expected patterns of biodiversity under random sampling that allows integrating analyses across -, {gamma}-, and {beta}-scales. Importantly, the method can accommodate comparisons between communities with different species pool sizes, and can be used to examine species turnover both within and between meta-communities. Open Research statement: all code and data used in this manuscript are available at the following link: https://github.com/MoBiodiv/beta_concept

ecology↗

bioRxiv2023

Immunoproteasome deficiency results in accelerated brain aging and epilepsy

The immunoproteasome is a central protease complex required for optimal antigen presentation. Immunoproteasome activity is also associated with facilitating degradation of misfolded and oxidized proteins, which prevents cellular stress. While extensively studied during diseases with increasing evidence suggesting a role for the immunoproteasome during pathological conditions including neurodegenerative diseases, this enzyme complex is believed to be mainly inactive in the healthy brain. Here, we show an age-dependent increase in polyubiquitination in the brain of wild-type mice, accompanied with induction of immunoproteasomes, which was most prominent in neurons and microglia. In contrast, mice completely lacking immunoproteasomes (triple-knockout (TKO) mice deficient for LMP2, LMP7 and MECL-1), displayed a strong increase in polyubiquitinated proteins already in the young brain and developed spontaneous epileptic seizures, beginning at the age of 6 months. Injections of kainic acid led to high epilepsy-related mortality of aged TKO mice, confirming increased pathological hyperexcitability states. Notably, the expression of the immunoproteasome was reduced in the brains of patients suffering from epilepsy. In addition, aged TKO mice showed increased anxiety, tau hyperphosphorylation and degeneration of Purkinje cell population with the resulting ataxic symptoms and locomotion alterations. Collectively, our study suggests a critical role for the immunoproteasome in the maintenance of a healthy brain during aging.

neuroscience↗

bioRxiv2022

A role for myeloid miR-155 in regulating hypoxia induced seizures in neonatal C57BL/J6 mice

Hypoxic ischaemic injury (HIE) in the neonatal brain has significant consequences on neurodevelopment and increases the occurrence of neurological deficits in infants. HIE is also a leading cause of neonatal seizures. Therapeutic options for the treatment of HIE are very limited. Hypoxia-ischemia directly damages brain tissue in a primary-wave of injury which activates a cascade of events triggering local and systemic inflammatory responses, driven by the innate immune system, which contribute to a significant secondary-wave of injury taking place as early as 6 hours post-hypoxia-ischaemia. Levels of the well documented inflammatory microRNA, miR-155 are elevated in rodent seizure and epilepsy models. Here, we assessed the impact of, miR-155 deletion in myeloid cells, on regulating inflammation and seizure severity in a preclinical model of neonatal hypoxia-induced seizures (Hypoxia-Sz). Wildtype miR-155 (miR-155+/+LysMCre) mice were compared to a mouse line in which miR-155 was deleted in myeloid cells (miR-155fl/fl LysMCre). We demonstrate significant upregulation of miR-155 target genes, brain-derived neurotrophic factor (bdnf), arginase-2 (arg-2), ship-1 and socs-1 in miR-155fl/fl LysMCre mice compared to controls at various time points following Hypoxia-Sz. Conversely, we report decreased mRNA levels of pro-inflammatory cytokines IL-1{beta} and IL-6 and lower protein levels of IL-1{beta} in miR-155fl/fl LysMCre mice as compared to WTs. Myeloid miR-155 deletion significantly reduced behavioural seizure severity score, reduced electrographically (EEG) measured seizure frequency and seizure burden as compared to mice to wildtypes, suggesting miR-155 regulation of seizure occurrence in this model. Behavioural tests for motor functions at 5 weeks post Hypoxia-Sz demonstrated differences between genotypes. Excitingly this work highlights that inhibition of miR-155, specifically in myeloid cells, may hold therapeutic benefit for both seizures and comorbidities associated with hypoxic brain injury.

neuroscience↗

bioRxiv2022

Synthesis reveals biotic homogenisation and differentiation are both common

It is commonly thought that the biodiversity crisis includes widespread decreases in the uniqueness of different sites in a landscape (biotic homogenization). Using a typology relating homogenization and differentiation to local and regional diversity changes, we synthesize patterns across 283 metacommunities surveyed for 10-91 years, and 54 species checklists (13-500+ years). On average, there is a 0.2% increase in species shared among communities/year (i.e., weak homogenization), but across data sets, differentiation frequently occurs, with no statistically significant change being most common. Local (not regional) diversity frequently underlies composition change, and homogenization is strongly associated with checklist data that have longer durations and large spatial scales. Conservation and management can benefit from the multiscale perspective used here as it disentangles the implications of both the differentiation and homogenization currently unfolding. One-Sentence SummaryBiotic homogenization is most prevalent at large temporal and spatial scales.

ecology↗

bioRxiv2021

Local biodiversity change reflects interactions among changing abundance, evenness and richness

Biodiversity metrics often integrate data on the presence and abundance of multiple species. Yet understanding covariation of changes to the numbers of individuals, the evenness of species relative abundances, and the total number of species remains limited. Using individual-based rarefaction curves, we introduce a conceptual framework to understand how expected positive relationships among changes in abundance, evenness and richness arise, and how they can break down. We then examined interdependencies between changes in abundance, evenness and richness in more than 1100 assemblages sampled either through time or across space. As predicted, richness changes were greatest when abundance and evenness changed in the same direction, and countervailing changes in abundance and evenness acted to constrain the magnitude of changes in species richness. Site-to-site changes in abundance, evenness, and richness were often decoupled, and pairwise relationships between changes in these components across assemblages were weak. In contrast, changes in species richness and relative abundance were strongly correlated for assemblages varying through time. Temporal changes in local biodiversity showed greater inertia and stronger relationships between the component changes when compared to site-to-site variation. Local variation in assemblage diversity was rarely due to a passive sample from a more or less static species abundance distribution. Instead, changing species relative abundances often dominated local variation in diversity. Moreover, how changing relative abundances combined with changes to total abundance frequently determined the magnitude of richness changes. Embracing the interdependencies between changing abundance, evenness and richness can provide new information for better understanding biodiversity change in the Anthropocene.

ecology↗

bioRxiv2021

Functional expression of the ATP-gated P2X7 receptor in human iPSC-derived neurons and astrocytes

The P2X7 receptor (P2X7R) is a cation membrane channel activated by extracellular adenosine 5'-triphosphate. Activation of this receptor results in numerous downstream events including the modulation of neurotransmission, release of pro-inflammatory mediators, cell proliferation or cell death. While the expression of P2X7Rs is well documented on microglia and oligodendrocytes, the presence of functional P2X7Rs on neurons and astrocytes remains debated. Furthermore, to date, functional studies on the P2X7R are mostly limited to studies in cells from rodents and immortalised cell lines expressing human P2X7Rs. To assess the functional expression of P2X7Rs in human neurons and astrocytes, we differentiated human-induced pluripotent stem cells (hiPSCs) into forebrain cortical neurons that co-express FOXG1 and {beta}III-tubulin as well as S100 {beta}-expressing astrocytes. Immunostaining revealed prominent punctate P2X7R staining on the soma and processes of hiPSC-derived neurons and astrocytes. In addition, our data show that stimulation with the potent nonselective P2X7R agonist BzATP induces robust calcium rises in hiPSC-derived neurons and astrocytes, which were blocked by the selective P2X7R antagonist AFC-5128. Together, our findings provide evidence for the functional expression of P2X7Rs in hiPSC-derived forebrain cortical neurons and astrocytes demonstrating that these cells offer the potential for investigating P2X7R-mediated pathophysiology and drug screening in vitro.

neuroscience↗

bioRxiv2020

High concordance between hippocampal transcriptome of the intraamygdala kainic acid model and human temporal lobe epilepsy

ObjectivePharmacoresistance and the lack of disease-modifying actions of current anti-seizure drugs persist as major challenges in the treatment of epilepsy. Experimental models of chemoconvulsant-induced status epilepticus remain the models of choice to discover potential anti-epileptogenic drugs but doubts remain as to the extent to which they model human pathophysiology. The aim of the present study was to compare the molecular landscape of the intraamygdala kainic acid model of status epilepticus in mice with findings in resected brain tissue from patients with drug-resistant temporal lobe epilepsy (TLE). MethodsStatus epilepticus was induced via intraamygdala microinjection of kainic acid in C57BL/6 mice and gene expression analysed via microarrays in hippocampal tissue at acute and chronic time-points. Results were compared to reference datasets in the intraperitoneal pilocarpine and intrahippocampal kainic acid model and to human resected brain tissue (hippocampus and cortex) from patients with drug-resistant TLE. ResultsIntraamygdala kainic acid injection in mice triggered extensive dysregulation of gene expression which was [~]3-fold greater shortly after status epilepticus (2729 genes) when compared to epilepsy (412). Comparison to samples of patients with TLE revealed a particular high correlation of gene dysregulation during established epilepsy. Pathway analysis found suppression of calcium signalling to be highly conserved across different models of epilepsy and patients. CREB was predicted as one of the main up-stream transcription factors regulating gene expression during acute and chronic phases and inhibition of CREB reduced seizure severity in the intraamygdala kainic acid model. SignificanceOur findings suggest the intraamygdala kainic acid model faithfully replicates key molecular features of human drug-resistant temporal lobe epilepsy and provides potential rationale target approaches for disease-modification through new insights into the unique and shared gene expression landscape in experimental epilepsy. Key point boxO_LIMore genes show expression changes shortly following intraamygdala kainic acid-induced status epilepticus when compared to established epilepsy. C_LIO_LIThe intraamygdala kainic acid mouse model mimics closely the gene expression landscape in the brain of patients with temporal lobe epilepsy. C_LIO_LISupressed calcium signalling in the brain as common feature across experimental models of epilepsy and patients with temporal lobe epilepsy. C_LIO_LICREB is a major up-stream transcription factor during early changes following status epilepticus and once epilepsy is established. C_LI

neuroscience↗

bioRxiv2020

Resolving the species pool dependence of beta-diversity using coverage-based rarefaction

Understanding how species are non-randomly distributed in space, as well as how the resulting spatial structure of diversity responds to ecological, biogeographic and anthropogenic drivers is a critical piece of the biodiversity puzzle. However, most metrics that quantify the spatial structure of diversity (i.e., community differentiation), such as Whittakers classical {beta}-diversity metric are influenced by sampling effects. As a result, these measures are influenced by species pool size, species abundance distributions and numbers of individuals. Null models have been proposed to evaluate the degree of differentiation among communities due to spatial structuring relative to that expected from sampling effects. However, to date, these null models do not accommodate the influence of sample completeness (i.e. the proportion of the species pool in the sample). Here, we develop an approach that makes use of individual- and coverage-based rarefaction and extrapolation. Using spatially explicit simulations, we show that our derived metric, {beta}C, captures changes in intraspecific aggregation independently of changes in the species pool size. We then provide two case studies examining spatial structure in forest plots spanning latitudinal gradients: (1) a re-analysis of the "Gentry" plot dataset, and (2) comparing a high diversity plot in Barro Colorado Island, Panama with a low diversity plot in Harvard Forest, Massachusetts, USA. We find no evidence for systematic changes in spatial structure with latitude in these datasets. As it is rooted in biodiversity sampling theory and explicitly controls for sample completeness, our approach represents an important advance over existing null models for spatial aggregation. Potential applications of the approach range from better descriptors of biogeographic diversity patterns to the consolidation of local and regional diversity trends in the current biodiversity crisis. Open research statementThe novel code for the calculation of {beta}C can be found in supplementary material S4. Empirical data sets utilized for this research are as follows: Phillips & Miller (2002), Orwig et al. (2015), Condit et al. (2019). Our research repository including the novel code is also available at https://github.com/t-engel/betaC and will be uploaded to Zenodo upon acceptance of this manuscript.

ecology↗

bioRxiv2020

Top-down coordination of local cortical state during selective attention

Spontaneous fluctuations in cortical excitability influence sensory processing and behavior. These fluctuations, long known to reflect global changes in cortical state, were recently found to be modulated locally within a retinotopic map during spatially selective attention. We found that periods of vigorous (On) and faint (Off) spiking activity, the signature of cortical state fluctuations, were coordinated across brain areas along the visual hierarchy and tightly coupled to their retinotopic alignment. During top-down attention, this interareal coordination was enhanced and progressed along the reverse cortical hierarchy. The extent of local state coordination between areas was predictive of behavioral performance. Our results show that cortical state dynamics are shared across brain regions, modulated by cognitive demands and relevant for behavior. One Sentence SummaryInterareal coordination of local cortical state is retinotopically precise and progresses in a reverse hierarchical manner during selective attention.

neuroscience↗

bioRxiv2019

A multiscale framework for disentangling the roles of evenness, density and aggregation on diversity gradients

Disentangling the drivers of diversity gradients can be challenging. The Measurement of Biodiversity (MoB) framework decomposes changes in species diversity into three components of community structure: the species abundance distribution (SAD), the total community abundance, and the within-species spatial aggregation. Here we extend MoB from categorical treatment comparisons to quantify variation along continuous geographic or environmental gradients. Our approach requires sites along a gradient, each consisting of georeferenced plots of abundance-based species composition data. We demonstrate our method using a case study of ants sampled along an elevational gradient of 28 sites in mixed deciduous forest of the Great Smoky Mountains National Park, USA. MoB analysis revealed that ant species richness decreased along the elevational gradient because of changes in the SAD and in spatial aggregation, but not because of changes in the number of individuals. Specifically, with increasing elevation, species evenness was lower and species were less aggregated. These results do not support the more-individuals hypothesis; alternative hypotheses are required to explain why evenness and aggregation decrease with elevation. Our extension of MoB has the potential to elucidate the drivers of diversity along environmental gradients and should be useful for a variety of assemblage-level data collected along gradients.

ecology↗

bioRxiv2019

A systems approach delivers a functional microRNA catalog and expanded targets for seizure suppression in temporal lobe epilepsy

MicroRNAs (miRNAs) are short noncoding RNAs that shape the gene expression landscape, including during the pathogenesis of temporal lobe epilepsy (TLE). In order to provide a full catalog of the miRNA changes that happen during experimental TLE, we sequenced Argonaute 2-loaded miRNAs in the hippocampus of three different animal models at regular intervals between the time of the initial precipitating insult to the establishment of spontaneous recurrent seizures. The commonly upregulated miRNAs were selected for a functional in vivo screen using oligonucleotide inhibitors. This revealed anti-seizure phenotypes upon inhibition of miR-10a-5p, miR-21a-5p and miR-142a-5p as well as neuroprotection-only effects for inhibition of miR-27a-3p and miR-431-5p. Proteomic data and pathway analysis on predicted and validated targets of these miRNAs indicated a role for TGF{beta} signaling in a shared seizure-modifying mechanism. Together, these results identify functional miRNAs in the hippocampus and a pipeline of new targets for seizure control in epilepsy.

neuroscience↗

bioRxiv2019

Large-scale changes to mRNA polyadenylation in temporal lobe epilepsy

The molecular mechanisms that shape the gene expression landscape during the development and maintenance of chronic states of brain hyperexcitability are incompletely understood. Here we show that cytoplasmic mRNA polyadenylation, a posttranscriptional mechanism for regulating gene expression, undergoes widespread reorganisation in temporal lobe epilepsy. Specifically, over 25% of the hippocampal transcriptome displayed changes in their poly(A) tail in mouse models of epilepsy, particular evident in the chronic phase. The expression of cytoplasmic polyadenylation binding proteins (CPEB1-4) was found to be altered in the hippocampus in mouse models of epilepsy and temporal lobe epilepsy patients and CPEB4 target transcripts were over-represented among those showing poly(A) tail changes. Supporting an adaptive function, CPEB4-deficiency leads to an increase in seizure severity and neurodegeneration in mouse models of epilepsy. Together, these findings reveal an additional layer of gene expression control during epilepsy and point to novel targets for seizure control and disease-modification in epilepsy.

neuroscience↗

bioRxiv2017

Computational Model for Simulating Drug-Induced Arrhythmia Sensitivity of Human iPSC-derived Cardiomyocytes

A mathematical model describing the electrophysiology and ion handling of cardiomyocytes is a complement to experimental analysis predicting drug-induced proarrhythmic potential in humans as proposed by Comprehensive in vitro Proarrhythmia Assay (CiPA). While CiPA endorses the use of the OHara Rudy (ORd) model, which was developed to simulate electrophysiology of human adult ventricular cardiomyocytes (hAVCMs), to predict drug-induced proarrhythmias; the human induced pluripotent stem cell derived-cardiomyocytes (hiPSC-CMs) was proposed for experimental verifications. The hiPSC-CMs, especially cultured in 2D culture dishes, are inherently different from hAVCMs exhibiting different ion channel density and an immature sarcoplasmic reticulum function. To reconcile this mismatch, we have developed a mathematical electrophysiology model of an hiPSC-CM by incorporating differences in gene expressions of ion channels, pumps and receptors in hiPSC-CMs against those found in hAVCMs. This model can be used to model any hiPSC-CM cell line where expression data has been obtained and replaces the background currents for K+ and Na+ in the ORd model with the known ultra-rapid K+ channel and hyperpolarization activated K+/Na+ channel currents. With this new model, three batches each from two different hiPSC-CM cell lines are compared to experimental data of action potential duration. This mathematical model recapitulates a ventricular-like action potential morphology with a Phase 2 plateau lasting a few hundred milliseconds. However, the resting membrane potential is not as depolarized (-65 to -70 mV) as that of hAVCM (-80 mV). The elevated resting membrane potential matches experimental data previously and is thought to keep rapid sodium channels from triggering membrane depolarization instead being replaced by an overexpression of L-Type Ca2+ channel current. This model is a key step in identifying the variability between different hiPSC-CM lines and even batches of the same line, opening the door to realizing analysis of patient specific preparations in the future.

physiology↗