Biology subjects

Aerts, H.

Publications and source records attributed to Aerts, H..

6 recordsLinked to original sources

bioRxiv2019

Catalysis by a rigid enzyme

Many enzymes are dynamic entities, sampling conformational states that are relevant for catalytic activity. Crystal structures of catalytic intermediates suggest, however, that not all enzymes require structural changes for activity. The single-domain enzyme xylanase from Bacillus circulans (BCX) is involved in the degradation of hemicellulose. We demonstrate that BCX in solution undergoes minimal structural changes during catalysis. NMR spectroscopy results show that the rigid protein matrix provides a frame for fast substrate binding in multiple conformations, accompanied by slow, enzyme induced substrate distortion. Therefore, we propose a model in which the rigid enzyme takes advantage of substrate flexibility to induce a conformation that facilitates catalysis.\n\nOne Sentence SummaryThe rigid matrix of BCX uses substrate flexibility in Michaelis complex formation.

biochemistry↗

bioRxiv2019

Modeling brain dynamics after tumor resection using The Virtual Brain

Brain tumor patients scheduled for tumor resection often face significant uncertainty, as the outcome of neurosurgery is difficult to predict at the individual patient level. Recently, computational modeling of brain activity using so-called brain network models has been introduced as a promising tool for this purpose. However, brain network models first have to be validated, before they can be used to predict brain dynamics. In prior work, we optimized individual brain network model parameters to maximize the fit with empirical brain activity. In this study, we extend this line of research by examining the stability of fitted parameters before and after tumor resection, and compare it with baseline parameter variability using data from healthy control subjects. Based on these findings, we perform the first \"virtual neurosurgery\" analyses to evaluate the potential of brain network modeling in predicting brain dynamics after tumor resection.\n\nWe find that brain network model parameters are relatively stable over time in brain tumor patients who underwent tumor resection, compared with baseline variability in healthy control subjects. In addition, we identify several robust associations between individually optimized model parameters, structural network topology and cognitive performance from pre-to post-operative assessment. Concerning the virtual neurosurgery analyses, we obtain promising results in some patients, whereas the predictive accuracy of the currently applied model is poor in others. These findings reveal interesting avenues for future research, as well as important limitations that warrant further investigation.

neuroscience↗

bioRxiv2019

Evaluating the performance of 3-tissue constrained spherical deconvolution pipelines for within-tumor tractography

The use of diffusion MRI (dMRI) for assisting in the planning of neurosurgery has become increasingly common practice, allowing to non-invasively map white matter pathways via tractography techniques. Limitations of earlier pipelines based on the diffusion tensor imaging (DTI) model have since been revealed and improvements were made possible by constrained spherical deconvolution (CSD) pipelines. CSD allows to resolve a full white matter (WM) fiber orientation distribution (FOD), which can describe so-called \"crossing fibers\": complex local geometries of WM tracts, which DTI fails to model. This was found to have a profound impact on tractography results, with substantial implications for presurgical decision making and planning. More recently, CSD itself has been extended to allow for modeling of other tissue compartments in addition to the WM FOD, typically resulting in a 3-tissue CSD model. It seems likely this may improve the capability to resolve WM FODs in the presence of infiltrating tumor tissue. In this work, we evaluated the performance of 3-tissue CSD pipelines, with a focus on within-tumor tractography. We found that a technique named single-shell 3-tissue CSD (SS3T-CSD) successfully allowed tractography within infiltrating gliomas, without increasing existing single-shell dMRI acquisition requirements.

neuroscience↗

bioRxiv2018

Modeling brain dynamics in brain tumor patients using The Virtual Brain

Presurgical planning for brain tumor resection aims at delineating eloquent tissue in the vicinity of the lesion to spare during surgery. To this end, non-invasive neuroimaging techniques such as functional MRI and diffusion weighted imaging fiber tracking are currently employed. However, taking into account this information is often still insufficient, as the complex non-linear dynamics of the brain impede straightforward prediction of functional outcome after surgical intervention. Large-scale brain network modeling carries the potential to bridge this gap by integrating neuroimaging data with biophysically based models to predict collective brain dynamics.\n\nAs a first step in this direction, an appropriate computational model has to be selected, after which suitable model parameter values have to be determined. To this end, we simulated large-scale brain dynamics in 25 human brain tumor patients and 11 human control participants using The Virtual Brain, an open-source neuroinformatics platform. Local and global model parameters of the Reduced Wong-Wang model were individually optimized and compared between brain tumor patients and control subjects. In addition, the relationship between model parameters and structural network topology and cognitive performance was assessed.\n\nResults showed (1) significantly improved prediction accuracy of individual functional connectivity when using individually optimized model parameters; (2) local model parameters can differentiate between regions directly affected by a tumor, regions distant from a tumor, and regions in a healthy brain; and (3) interesting associations between individually optimized model parameters and structural network topology and cognitive performance.

bioinformatics↗

bioRxiv2018

Predicting functional networks from region connectivity profiles in task-based versus resting-state fMRI data

Intrinsic Connectivity Networks, patterns of correlated activity emerging from \"resting-state\" Blood Oxygenation Level Dependent time series, are increasingly being associated to cognitive, clinical, and behavioral aspects, and compared with the pattern of activity elicited by specific tasks. We study the reconfiguration of the brain networks between task and resting-state conditions by a machine learning approach, to highlight the Intrinsic Connectivity Networks (ICNs) which are more affected by the change of network configurations in task vs. rest. We use a large cohort of publicly available data in both resting and task-based fMRI paradigms; by trying a battery of different supervised classifiers relying only on task-based measurements, we show that the highest accuracy is reached with a simple neural network of one hidden layer. In addition, when testing the fitted model on resting state measurements, such architecture yields a performance close to 90% for areas connected to the task performed, which mainly involve the visual and sensorimotor cortex, whilst a relevant decrease of the performance is observed in the other ICNs. On one hand, our results confirm the correspondence of ICNs in both paradigms (task and resting) thus opening a window for future clinical applications to subjects whose participation in a required task cannot be guaranteed. On the other hand it is shown that brain areas not involved in the task display different connectivity patterns in the two paradigms.

neuroscience↗

bioRxiv2017

Histopathological image QTL discovery of thyroid autoimmune disease variants

Genotype-to-phenotype association studies typically use macroscopic physiological measurements or molecular readouts as quantitative traits. There are comparatively few suitable quantitative traits available between cell and tissue length scales, a limitation that hinders our ability to identify variants affecting phenotype at many clinically informative levels. Here we show that quantitative image features, automatically extracted from histopathological imaging data, can be used for image Quantitative Trait Loci (iQTL) mapping and variant discovery. Using thyroid pathology images, clinical metadata, and genomics data from the Genotype and Tissue Expression (GTEx) project, we establish and validate a quantitative imaging biomarker for immune cell infiltration. A total of 100,215 variants were selected for iQTL profiling, and tested for genotype-phenotype associations with our quantitative imaging biomarker. Significant associations were found in HDAC9 and TXNDC5. We validated the TXNDC5 association using GTEx cis-expression QTL data, and an independent hypothyroidism dataset from the Electronic Medical Records and Genomics network.\n\nOne Sentence SummaryWe use a histopathological image QTL analysis to identify genomic variants associated with immune cell infiltration.

genomics↗