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Biology subjects

Stallinga, S.

Publications and source records attributed to Stallinga, S..

13 recordsLinked to original sources

Absorption dipole effects on MINFLUX single molecule localization

Single molecule fluorescence localization with minimum photon flux imaging (MINFLUX) can achieve localization precisions in the small nanometer range or better under suitable conditions. Potentially adverse conditions, such as a fixed fluorescence dipole or optical aberrations, that could cause systematic localization errors, have received little attention up to now. Here, we study these effects in simulation. We find that biases occur for fluorophores with a fixed absorption dipole tilted out of the imaging plane. These become larger (up to about 25% of the diameter of the circle spanned by the doughnut center positions) the larger the tilt angle gets. As a rule of thumb the spread in bias is smaller than 5 nm in case the dipole orientation is less than 30{degrees} out of plane for the typical case of a doughnut probing circle of diameter 100 nm. For freely rotating dipoles only the primary aberrations astigmatism and coma contribute to bias. This bias depends on the position of the fluorophore inside the circular probing area of MINFLUX and can be significantly larger than the localization precision. We show that increasing the number of measurements over the circle from a triangular to a hexagonal pattern is beneficial for reducing bias in all cases. Iterative shrinking of the probing area can eliminate the position dependent bias completely, but a strong dependence on dipole orientation of the bias at the center of the probing area remains.

biophysics↗

Calibration-free estimation of field dependent aberrations for single molecule localization microscopy across large fields of view

Image quality in single molecule localization microscopy (SMLM) depends largely on the accuracy and precision of the localizations. While under ideal imaging conditions the theoretically obtainable precision and accuracy are achieved, in practice this changes if (field dependent) aberrations are present. Currently there is no simple way to measure and incorporate these aberrations into the Point Spread Function (PSF) fitting, therefore the aberrations are often taken constant or neglected all together. Here we introduce a model-based approach to estimate the field-dependent aberration directly from single molecule data without a calibration step. This is made possible by using nodal aberration theory to incorporate the field-dependency of aberrations into our fully vectorial PSF model. This results in a limited set of aberration fit parameters that can be extracted from the raw frames without a bead calibration measurement, also in retrospect. The software implementation is computationally efficient, enabling fitting of a full 2D or 3D dataset within a few minutes. We demonstrate our method on 2D and 3D localization data of microtubuli and nuclear pore complexes over fields of view (FOV) of up to 180 m and compare it with spline-based fitting and a deep learning based approach.

microbiology↗

Smart 3D super-resolution microscopy reveals the architecture of the RNA scaffold in a nuclear body

Small subcellular organelles orchestrate key cellular functions. How biomolecules are spatially organized within these assemblies is poorly understood. Here, we report an automated super- resolution imaging and analysis workflow that integrates confocal microscopy, morphological object screening, targeted 3D super-resolution STED microscopy and quantitative image analysis. Using this smart microscopy workflow, we targeted the 3D organization of an architectural RNA that constitutes the structural backbone of paraspeckles, a membraneless nuclear organelle. Using site-specific labeling, morphological sorting and particle averaging, we reconstructed the morphological space of paraspeckles along their development cycle from over 10,000 individual particles. Applying spherical harmonics analysis, we report so-far unknown heterotypes of RNA organization. By integrating multi- positional labeling, we determined the coarse conformation of the RNA within the organelle and found the 3 end forming a loop-like structure at the surface of the paraspeckle. Our study reveals key structural features of nuclear paraspeckle structure and growth, as well as on the molecular organization of the scaffold RNA.

biophysics↗

Particle fusion of Single Molecule Localization Microscopy data reveals dimer structure of Nup96 in Nuclear Pore Complex

Single molecule localization microscopy offers nowadays resolution nearly down to the molecular level with specific molecular labelling, thereby being a promising tool for structural biology. In practice, however, the actual value to this field is limited primarily by incomplete fluorescent labeling of the structure. This missing information can be completed by merging information from many structurally identical particles equivalent to cryo-EM single-particle analysis. In this analysis, we present particle averaging of fluorescently labelled Nup96 in the Nuclear Pore Complex followed by data analysis to show that Nup96 occurs as a dimer with in total 32 copies per pore. We use Artificial Intelligence assisted modeling in Alphafold to extend the existing cryo-EM model of Nup96 to accurately pinpoint the positions of the fluorescent labels and show the accuracy of the match between fluorescent and cryo-EM data to be better than 3 nm in-plane and 5 nm out-of-plane.

cell biology↗

Joint Registration of Multiple Point Clouds for Fast Particle Fusion in Localization Microscopy

We present a fast particle fusion method for particles imaged with single-molecule localization microscopy. The state-of-the-art approach based on all-to-all registration has proven to work well but its computational cost scales unfavourably with the number of particles N, namely as N2. Our method overcomes this problem and achieves a linear scaling of computational cost with N by making use of the Joint Registration of Multiple Point Clouds (JRMPC) method. Straightforward application of JRMPC fails as mostly locally optimal solutions are found. These usually contain several overlapping clusters, that each consist of well-aligned particles, but that have different poses. We solve this issue by repeated runs of JRMPC for different initial conditions, followed by a classification step to identify the clusters, and a connection step to link the different clusters obtained for different initializations. In this way a single well-aligned structure is obtained containing the majority of the particles. We achieve reconstructions of experimental DNA-origami datasets consisting of close to 400 particles within only 10 min on a CPU, with an image resolution of 3.2 nm. In addition, we show artifact-free reconstructions of symmetric structures without making any use of the symmetry. We also demonstrate that the method works well for poor data with a low density of labelling and for 3D data.

bioinformatics↗

Structured illumination microscopy with noise-controlled image reconstructions

Super-resolution structured illumination microscopy (SIM) has become a widely used method for biological imaging. Standard reconstruction algorithms, however, are prone to generate noise-specific artefacts that limit their applicability for lower signal-to-noise data. Here, we present a physically realistic noise model that explains the structured noise artefact and that is used to motivate new complementary reconstruction approaches. True Wiener-filtered SIM optimizes contrast given the available signal-to-noise ratio, flat-noise SIM fully overcomes the structured noise artefact while maintaining resolving power. Both methods eliminate ad-hoc user adjustable reconstruction parameters in favour of physical parameters, enhancing objectivity. The new reconstructions point to a trade-off between contrast and a natural noise appearance. This trade-off can be partly overcome by additional notch filtering, but at the expense of a decrease in signal-to-noise ratio. The benefits of the proposed approaches are demonstrated on focal adhesion and tubulin samples in 2D and 3D, and on nano-fabricated fluorescent test patterns.

biophysics↗

High-speed, multicolor, structured illumination microscopy using a hexagonal single mode fiber array

Structured Illumination Microscopy (SIM) is a widely used imaging technique that doubles the effective resolution of widefield microscopes. Most current implementations rely on diffractive elements, either gratings or programmable devices, to generate structured light patterns in the sample. These can be limited by spectral efficiency, speed, or both. Here we introduce the concept of fiber SIM which allows for camera frame rate limited pattern generation and manipulation over a broad wavelength range. Illumination patterns are generated by coupling laser beams into radially opposite pairs of fibers in a hexagonal single mode fiber array where the exit beams are relayed to the microscope objectives back focal plane. The phase stepping and rotation of the illumination patterns are controlled by fast electro-optic devices. We achieved a rate of 111 SIM frames per second and imaged with excitation patterns generated by both 488 nm and 532 nm lasers.

cell biology↗

Simultaneous orientation and 3D localization microscopy with a Vortex point spread function

We have developed an engineered Point Spread Function (PSF) to enable the simultaneous estimation of dipole orientation, 3D position and degree of rotational constraint of single-molecule emitters from a single 2D focal plane. Besides giving access to orientation information, the Vortex PSF along with the vectorial PSF fitter avoids localization bias common in localization microscopy for fixed dipole emitters. We demonstrate this technique on reorienting single-molecules and using binding-activated localization microscopy on DNA intercalators, corroborating perpendicular azimuthal angles to the DNA axis for in-plane emitters but find a non-uniform distribution as a function of the polar angle. The Vortex PSF is realized by an affordable glass phase mask and has a compact footprint that can easily be combined with localization microscopy techniques on rotationally constrained emitters.

molecular biology↗

Three dimensional particle averaging for structural imaging of macromolecular complexes by localization microscopy

We present an approach for 3D particle fusion in localization microscopy which dramatically increases signal-to-noise ratio and resolution in single particle analysis. Our method does not require a structural template, and properly handles anisotropic localization uncertainties. We demonstrate 3D particle reconstructions of the Nup107 subcomplex of the nuclear pore complex (NPC), cross-validated using multiple localization microscopy techniques, as well as two-color 3D reconstructions of the NPC, and reconstructions of DNA-origami tetrahedrons.

molecular biology↗

Localization microscopy at doubled precision with patterned illumination

MINFLUX offers a breakthrough in single molecule localization precision, but suffers from a tiny field-of-view and a lack of practical parallelism. Here, we combine centroid estimation and illumination pattern induced photon count variations in a conventional widefield imaging setup to extract position information over a typical micron sized field-of-view. We show a near twofold improvement in precision over standard localization with the same photon count on DNA-origami nano-structures.

molecular biology↗

Photon count estimation in single-molecule localization microscopy

Recently, Franke, Sauer and van de Linde1 introduced a way to estimate the axial position of single-molecules (TRABI). To this end, they compared the detected photon count from a temporal radial-aperture-based intensity estimation to the estimated count from Gaussian point-spread function (PSF) fitting to the data. Empirically they found this photometric ratio to be around 0.7-0.8 close to focus and decreasing away from it. Here, we explain this reported but unexplained discrepancy and furthermore show that the photometric ratio as indicator for axial position is susceptible even to typical optical aberrations.

molecular biology↗

High precision wavefront control in Point Spread Function engineering for single emitter localization

Point spread function (PSF) engineering is used in single emitter localization to measure the emitter position in 3D and possibly other parameters such as the emission color or dipole orientation as well. Advanced PSF models such as spline fits to experimental PSFs or the vectorial PSF model can be used in the corresponding localization algorithms in order to model the intricate spot shape and deformations correctly. The complexity of the optical architecture and fit model makes PSF engineering approaches particularly sensitive to optical aberrations. Here, we present a calibration and alignment protocol for fluorescence microscopes equipped with a spatial light modulator (SLM) with the goal of establishing a wavefront error well below the diffraction limit for optimum application of complex engineered PSFs. We achieve high-precision wavefront control, to a level below 20 m{lambda} wavefront aberration over a 30 minute time window after the calibration procedure, using a separate light path for calibrating the pixel-to-pixel variations of the SLM, and alignment of the SLM with respect to the optical axis and Fourier plane within 3 {micro}m (x/y) and 100 {micro}m (z) error. Aberrations are retrieved from a fit of the vectorial PSF model to a bead z-stack and compensated with a residual wavefront error comparable to the error of the SLM calibration step. This well-calibrated and corrected setup makes it possible to create complex 3D+{lambda} PSFs that fit very well to the vectorial PSF model. Proof-of-principle bead experiments show precisions below 10 nm in x, y, and{lambda} , and below 20 nm in z over an axial range of 1 {micro}m with 2000 signal photons and 12 background photons.

biophysics↗

Fluorescence polarization control for on-off switching of single molecules at cryogenic temperatures

Light microscopy allowing sub-diffraction limited resolution has been among the fastest developing techniques at the interface of biology, chemistry and physics. Intriguingly no theoretical limit exists on how far the underlying measurement uncertainty can be lowered. In particular data fusion of large amounts of images can reduce the measurement error to match the resolution of structural methods like cryo-electron microscopy. Fluorescence, although reliant on a reporter molecule and therefore not the first choice to obtain ultra resolution structures, brings highly specific labeling of molecules in a large assemble to the table and inherently allows the detection of multiple colors, which enable the interrogation of multiple molecular species at the same time in the same sample. Here we discuss the problems to be solved in the coming years to aim for higher resolution and describe what polarization depletion of fluorescence at cryogenic temperatures can contribute for fluorescence imaging of biological samples like whole cells.

biophysics↗