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Glioblastoma is a very aggressive tumor and represents the most common primary brain malignancy. Key characteristics include its high resistance against conventional treatments, such as radio- and chemotherapy and its diffuse tissue infiltration, preventing complete surgical resection. The analysis of migration and invasion processes in a physiological microenvironment allows for enhanced understanding of these processes and can lead to improved therapeutic approaches. Here, we combine two state-of-the-art techniques, adult organotypic brain tissue slice culture (OTC) and light sheet fluorescence microscopy (LSFM) of cleared tissues in a combined method termed OTCxLSFM. Using this methodology, we can show that glioblastoma tissue infiltration can be effectively blocked through treatment with arsenic trioxide, as well as genetic depletion of the tetraspanin, transmembrane receptor CD9. With our analysis-pipeline we gain single-cell level, three-dimensional information, as well as insights into the morphological appearance of the tumor cells.
Sensory processing relies on interactions between excitatory and inhibitory neurons, which are often coordinated by 30-80Hz gamma oscillations. However, the specific contributions of distinct interneurons to gamma synchronization remain unclear. We performed high-density recordings from V1 in awake mice and used optogenetics to identify PV+ (Parvalbumin) and Sst+ (Somatostatin) interneurons. PV interneurons were highly phase-locked to visually-induced gamma oscillations. Sst cells were heterogeneous, with only a subset of narrow-waveform cells showing strong gamma phase-locking. Interestingly, PV interneurons consistently fired at an earlier phase in the gamma cycle (≈6ms or 60 degrees) than Sst interneurons. Consequently, PV and Sst activity showed differential temporal relations with excitatory cells. In particular, the 1st and 2nd spikes in burst events, which were strongly gamma phase-locked, shortly preceded PV and Sst activity, respectively. These findings indicate a primary role of PV interneurons in synchronizing excitatory cells and suggest that PV and Sst interneurons control the excitability of somatic and dendritic neural compartments with precise time delays coordinated by gamma oscillations.
VASP is a member of the Enabled/VASP protein family that is involved in cortical actin dynamics and may also contribute to the formation of gap junctions. In vessels, gap junctional coupling allows the transfer of signals along the vessel wall and coordinates vascular behavior. Moreover, VASP is reportedly a mediator of NO-induced inhibition of platelet aggregation. Therefore, we hypothesized that VASP exerts also important physiologic functions in arterioles. We examined the spread of vasodilations enabled by gap junctional coupling in endothelial cells as well as NO-induced arteriolar dilations in VASP-deficient mice by intravital microscopy of the microcirculation in a skeletal muscle in anesthetized mice. Conducted dilations were initiated by brief, locally confined stimulation of the arterioles with acetylcholine. The maximal diameters of the arterioles under study ranged from 30 to 40 μm. Brief stimulation with acetylcholine induced a short dilation at the local site that was also observed at remote, upstream sites without an attenuation of the amplitude up to a distance of 1.2 mm in control animals (wild-type). In contrast, remote dilations were reduced in VASP-deficient mice despite a similar local dilation indicating an impairment of conducted dilations. Superfusion of NOdonors induced a concentration-dependent dilation in wild-type mice. However, these dilations were slightly reduced in VASP-deficient animals. In contrast, dilations induced by the endothelial stimulator acetylcholine were fully preserved in VASP-deficient mice. In summary, this study suggests that VASP exerts critical functions in arteriolar diameter control. It is crucial for the conduction of dilator signals along the endothelial cell layer. The impairment possibly reflects a perturbed formation of gap junctions in the endothelial cell membrane. VASP also participates in the full dilatory potential of NOdonors although the effect of its deficiency is only subtle. In contrast, VASP is not required for dilations initiated by endothelial stimulation which are mediated in the murine microcirculation by an EDH-mechanism.
Dendritic spines are crucial for excitatory synaptic transmission as the size of a spine head correlates with the strength of its synapse. The distribution of spine head sizes follows a lognormal-like distribution with more small spines than large ones. We analysed the impact of synaptic activity and plasticity on the spine size distribution in adult-born hippocampal granule cells from rats with induced homo- and heterosynaptic long-term plasticity in vivo and CA1 pyramidal cells from Munc-13-1-Munc13-2 knockout mice with completely blocked synaptic transmission. Neither induction of extrinsic synaptic plasticity nor the blockage of presynaptic activity degrades the lognormal-like distribution but changes its mean, variance and skewness. The skewed distribution develops early in the life of the neuron. Our findings and their computational modelling support the idea that intrinsic synaptic plasticity is sufficient for the generation, while a combination of intrinsic and extrinsic synaptic plasticity maintains lognormal like distribution of spines.
Reliable, easy-to-handle phenotypic screening platforms are needed for the identification of anti-SARS-CoV-2 compounds. Here, we present caspase 3/7 activity as a readout for monitoring the replication of SARS-CoV-2 isolates from different variants, including a remdesivir-resistant strain, and of other coronaviruses in numerous cell culture models, independently of cytopathogenic effect formation. Compared to other models, the Caco-2 subline Caco-2-F03 displayed superior performance. It possesses a stable SARS-CoV-2 susceptibility phenotype and does not produce false-positive hits due to drug-induced phospholipidosis. A proof-of-concept screen of 1,796 kinase inhibitors identified known and novel antiviral drug candidates including inhibitors of phosphoglycerate dehydrogenase (PHGDH), CDC like kinase 1 (CLK-1), and colony stimulating factor 1 receptor (CSF1R). The activity of the PHGDH inhibitor NCT-503 was further increased in combination with the hexokinase II (HK2) inhibitor 2-deoxy-D-glucose, which is in clinical development for COVID-19. In conclusion, caspase 3/7 activity detection in SARS-CoV-2-infected Caco-2-F03 cells provides a simple phenotypic high-throughput screening platform for SARS-CoV-2 drug candidates that reduces false-positive hits.
Non-coding variations located within regulatory elements may alter gene expression by modifying Transcription Factor (TF) binding sites and thereby lead to functional consequences like various traits or diseases. To understand these molecular mechanisms, different TF models are being used to assess the effect of DNA sequence variations, such as Single Nucleotide Polymorphisms (SNPs). However, few statistical approaches exist to compute statistical significance of results but they often are slow for large sets of SNPs, such as data obtained from a genome-wide association study (GWAS) or allele-specific analysis of chromatin data.
Results We investigate the distribution of maximal differential TF binding scores for general computational models that assess TF binding. We find that a modified Laplace distribution can adequately approximate the empirical distributions. A benchmark on in vitro and in vivo data sets showed that our new approach improves on an existing method in terms of performance and speed. In applications on large sets of eQTL and GWAS SNPs we could illustrate the usefulness of the novel statistic to highlight cell type specific regulators and TF target genes.
Conclusions Our approach allows the evaluation of DNA changes that induce differential TF binding in a fast and accurate manner, permitting computations on large mutation data sets. An implementation of the novel approach is freely available at https://github.com/SchulzLab/SNEEP.
Motivation DNA CpG methylation (CpGm) has proven to be a crucial epigenetic factor in the gene regulatory system. Assessment of DNA CpG methylation values via whole-genome bisulfite sequencing (WGBS) is, however, computationally extremely demanding.
Results We present FAst MEthylation calling (FAME), the first approach to quantify CpGm values directly from bulk or single-cell WGBS reads without intermediate output files. FAME is very fast but as accurate as standard methods, which first produce BS alignment files before computing CpGm values. We present experiments on bulk and single-cell bisulfite datasets in which we show that data analysis can be significantly sped-up and help addressing the current WGBS analysis bottleneck for large-scale datasets without compromising accuracy.
Availability An implementation of FAME is open source and licensed under GPL-3.0 at https://github.com/FischerJo/FAME.
Human behaviour is inextricably linked to the interaction of emotion and cognition. For decades, emotion and cognition were perceived as separable processes, yet with mutual interactions. Recently, this differen-tiation has been challenged by more integrative approaches, but without addressing the exact neurophysiological basis of their interaction. Here, we aimed to uncover neurophysiological mechanisms of emotion-cognition interaction. We used an emotional Flanker task paired with EEG/FEM beamforming in a large cohort (N=121) of healthy human participants, obtaining high temporal and fMRI-equivalent spatial resolution. Spatially, emotion and cognition processing overlapped in the right inferior frontal gyrus (rIFG), specifically in pars triangularis. Temporally, emotion and cognition processing overlapped during the transition from emotional to cognitive processing, with a stronger interaction in β-band power leading to worse behavioral performance. Despite functionally segregated subdivisions in rIFG, frequency-specific information flowed extensively within IFG and top-down to visual areas (V2, Precuneus) – explaining the behavioral interference effect. Thus, for the first time we here show the neural mechanisms of emotion-cognition interaction in space, time, frequency and information transfer with high temporal and spatial resolution, revealing a central role for β-band activity in rIFG. Our results support the idea that rIFG plays a broad role in both inhibitory control and emotional interference inhibition as it is a site of convergence in both processes. Furthermore, our results have potential clinical implications for understanding dysfunctional emotion-cognition interaction and emotional interference inhibition in psychiatric disor-ders, e.g. major depression and substance use disorder, in which patients have difficulties in regulating emotions and executing inhibitory control.
Improved integration of single cell transcriptome data demonstrated on heart failure in mice and men
(2023)
Biomedical research frequently uses murine models to study disease mechanisms. However, the translation of these findings to human disease remains a significant challenge. In order to improve the comparability of mouse and human data, we present a cross-species integration pipeline for single-cell transcriptomic assays.
The pipeline merges expression matrices and assigns clear orthologous relationships. Starting from Ensembl ortholog assignments, we allocated 82% of mouse genes to unique orthologs by using additional publicly available resources such as Uniprot, and NCBI databases. For genes with multiple matches, we employed the Needleman-Wunsch global alignment based on either amino acid or nucleotide sequence to identify the ortholog with the highest degree of similarity.
The workflow was tested for its functionality and efficiency by integrating scRNA-seq datasets from heart failure patients with the corresponding mouse model. We were able to assign unique human orthologs to up to 80% of the mouse genes, utilizing the known 17,492 orthologous pairs. Curiously, the integration process enabled the identification of both common and unique regulatory pathways between species in heart failure.
In conclusion, our pipeline streamlines the integration process, enhances gene nomenclature alignment and simplifies the translation of mouse models to human disease. We have made the OrthoIntegrate R-package accessible on GitHub (https://github.com/MarianoRuzJurado/OrthoIntegrate), which includes the assignment of ortholog definitions for human and mouse, as well as the pipeline for integrating single cells.
Dendritic spines are considered a morphological proxy for excitatory synapses, rendering them a target of many different lines of research. Over recent years, it has become possible to image simultaneously large numbers of dendritic spines in 3D volumes of neural tissue. In contrast, currently no automated method for spine detection exists that comes close to the detection performance reached by human experts. However, exploiting such datasets requires new tools for the fully automated detection and analysis of large numbers of spines. Here, we developed an efficient analysis pipeline to detect large numbers of dendritic spines in volumetric fluorescence imaging data. The core of our pipeline is a deep convolutional neural network, which was pretrained on a general-purpose image library, and then optimized on the spine detection task. This transfer learning approach is data efficient while achieving a high detection precision. To train and validate the model we generated a labelled dataset using five human expert annotators to account for the variability in human spine detection. The pipeline enables fully automated dendritic spine detection and reaches a near human-level detection performance. Our method for spine detection is fast, accurate and robust, and thus well suited for large-scale datasets with thousands of spines. The code is easily applicable to new datasets, achieving high detection performance, even without any retraining or adjustment of model parameters.