Biology subjects

Mulder, M.

Publications and source records attributed to Mulder, M..

6 recordsLinked to original sources

bioRxiv2025

Time-resolved structures of β2-adrenergic receptor modulation by a photoswitchable beta-blocker

G protein-coupled receptors (GPCRs) regulate essential physiological responses and are important drug targets, yet their ligand-induced conformational dynamics remain poorly understood. The {beta}2-adrenergic receptor ({beta}2AR) is a prominent member of the GPCR family. It regulates bronchial and vascular function and is a significant drug target, particularly in respiratory and smooth muscle-related disorders. We employed time-resolved crystallography at X-ray free-electron lasers (XFELs) to capture the conformational dynamics of {beta}2AR bound to photoazolol-1, a beta-blocker derivative developed for photopharmacological applications. Structural snapshots of the receptor bound to trans-photoazolol-1 (pre-photoconversion), a strained intermediate, and the fully photoisomerized cis-photoazolol-1 reveal an intricate interplay between ligand chemistry and receptor plasticity. Isomerization of the azobenzene moiety induces distinct conformational changes within the orthosteric pocket, altering interactions with the extracellular loop 2 and transmembrane helices 5 and 6. Supported by functional assays, these structural shifts suggest that photoazolol-1 transitions from an inverse agonist to a neutral antagonist upon photoactivation. Our findings uncover a mechanism of GPCR modulation reminiscent of rhodopsin activation and offer a framework for designing ligands that harness light-driven transitions to achieve spatiotemporal control of receptor function.

biochemistry↗

bioRxiv2024

Structural insights into the opening mechanism of C1C2 channelrhodopsin

Channelrhodopsins, light-gated cation channels, enable precise control of neural cell depolarization or hyperpolarization with light in the field of optogenetics. This study integrates time-resolved serial crystallography and atomistic molecular dynamics (MD) simulations to resolve the structural changes during C1C2 channelrhodopsin activation. Our observations reveal that within the crystal environment, C1C2 predominantly remains in a light-activated state with characteristics of the M390 intermediate. Here, rearrangement of retinal within its binding pocket partially opens the central gate towards the extracellular vestibule. These structural changes initiate channel opening but were insufficient to allow K+ flow. Adjusting protonation states to represent the subsequent N520 intermediate in our MD simulations induced further conformational changes, including rearrangements of transmembrane helices 2 and 7, that opened the putative ion- translocation pathway. This allows spontaneous but low cation but not anion conduction, that matches experiments. Our findings provide critical structural insights into key intermediates of the channel opening mechanism, enhancing our understanding of ion conduction and selectivity in channelrhodopsins at an atomistic level.

biophysics↗

bioRxiv2021

No evidence for three functionally specialized subregions in the subthalamic nucleus: A model-based 7 T fMRI study

The subthalamic nucleus (STN) is a small, subcortical brain structure. It is a target for deep brain stimulation, an invasive treatment that reduces motor symptoms of Parkinsons disease. Side effects of DBS are commonly explained using the tripartite model of STN organization, which proposes three functionally distinct subregions in the STN specialized in cognitive, limbic, and motor processing. However, evidence for the tripartite model exclusively comes from anatomical studies and functional studies using clinical patients. Here, we provide the first experimental tests of the tripartite model in healthy volunteers using ultra-high field 7 Tesla (T) functional magnetic resonance imaging (fMRI). 34 participants performed a random-dot motion decision-making task with a difficulty manipulation and a choice payoff manipulation aimed to differentially affect cognitive and limbic networks. Moreover, participants responded with their left and right index finger, differentially affecting motor networks. We analysed BOLD signal in three subregions of equal volume of the STN along the dorsolateral-ventromedial axis, identified using manually delineated high resolution anatomical images. Our results indicate that all segments responded equally to the experimental manipulations, and did not support the tripartite model.

neuroscience↗

bioRxiv2020

3 versus 7 Tesla Magnetic Resonance Imaging for parcellations of subcortical brain structures

7 Tesla (7T) magnetic resonance imaging holds great promise for improved visualization of the human brain for clinical purposes. To assess whether 7T is superior regarding localization procedures of small brain structures, we compared manual parcellations of the red nucleus, subthalamic nucleus, substantia nigra, globus pallidus interna and externa, created on a commonly used clinical anisotropic clinical 3T with an optimized isotropic (o)3T and standard 7T scan. While the clinical 3T MRI scan did not allow delineation of an anatomical plausible structure due to its limited spatial resolution, optimized 3T and 7T parcellations could be directly compared. We found that 7T outperformed the o3T MRI as reflected by higher Dice scores, which were used as a measurement of interrater agreement for manual parcellations on quantitative susceptibility maps. This increase in agreement was associated with higher contrast to noise ratios for smaller structures, but not for the larger globus pallidus segments. Additionally, control-analyses were performed to account for potential biases in manual parcellations by assessing semi-automatic parcellations. These results did not confirm increased Dice scores for 7T, although they revealed a higher consistency for structure volumes for 7T compared to optimized 3T, potentially indicative of more agreement with increased field strength. Together these results indicate the importance of the use of isotropic voxels with both 3T and 7T, and the potential for clinical applications.

neuroscience↗

bioRxiv2020

Multi-contrast Anatomical Subcortical Structures Parcellation

The human subcortex is comprised of more than 450 individual nuclei which lie deep in the brain. Due to their small size and close proximity, up until now only 7% have been depicted in standard MRI atlases. Thus, the human subcortex can largely be considered as terra incognita. Here we present a new open source parcellation algorithm to automatically map the subcortex. The new algorithm has been tested on 17 prominent subcortical structures based on a large quantitative MRI dataset at 7 Tesla. It has been carefully validated against expert human raters and previous methods, and can easily be extended to other subcortical structures and applied to any quantitative MRI dataset. In sum, we hope this novel parcellation algorithm will facilitate functional and structural neuroimaging research into small subcortical nuclei and help to chart terra incognita.

neuroscience↗

bioRxiv2019

Denoising High-field Multi-dimensional MRI with Local Complex PCA

Modern high field and ultra high field magnetic resonance imaging (MRI) experiments routinely collect multi-dimensional data with high spatial resolution, whether multi-parametric structural, diffusion or functional MRI. While diffusion and functional imaging have benefited from recent advances in multi-dimensional signal analysis and denoising, structural MRI has remained untouched. In this work, we propose a denoising technique for multi-parametric quantitative MRI, combining a highly popular denoising method from diffusion imaging, over-complete local PCA, with a reconstruction of the complex-valued MR signal in order to define stable estimates of the noise in the decomposition. With this approach, we show signal to noise ratio (SNR) improvements in high resolution MRI without compromising the spatial accuracy or generating spurious perceptual boundaries.

bioinformatics↗