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Köhler, S.

Publications and source records attributed to Köhler, S..

12 recordsLinked to original sources

Investigating the role of the hippocampus in the implicit and explicit expression of statistical learning in patients with temporal lobe epilepsy

Statistical learning (SL) has been proposed to depend on the hippocampus, but traditional neuropsychological theories of long-term memory posit that the hippocampus is only necessary for explicit memory processes, not implicit memory processes. To reconcile these two accounts, we exposed 27 temporal lobe epilepsy (TLE) patients to a continuous speech stream containing embedded trisyllabic words, then tested their statistical knowledge using both implicit and explicit behavioural measures. TLE patients showed impairments on two explicit measures of SL alongside intact performance on an implicit measure of SL. These results suggest that the hippocampus may only be necessary for the explicit expression, but not the initial acquisition or implicit expression, of statistical knowledge.

neuroscience↗

NPP-21/TPR is required for developmental control of spindle checkpoint strength in C. elegans

The spindle checkpoint ensures accurate chromosome segregation by monitoring whether chromosomes, via kinetochores, are properly attached to the spindle. If chromosomes fail to establish bipolar attachment, the checkpoint delays the cell cycle to enable error correction. In C. elegans early embryos, activation of the spindle checkpoint produces a longer mitotic delay in primordial germ cells than somatic cells. We show that the conserved nucleoporin and spindle matrix component, NPP-21/TPR, is required for the stronger spindle checkpoint in germline cells. A checkpoint-proficient NPP-21::GFP transgene localizes to a spindle-like structure during mitosis and is enriched in germline cells, consistent with a cell-fate specific function for this protein. Finally, NPP-21 controls spindle checkpoint strength in germline cells via two, potentially linked, mechanisms: concentrating PCH-2 around mitotic chromosomes and promoting the localization of the checkpoint effector, Mad2, to unattached kinetochores. These experiments demonstrate a developmental role for NPP-21, and the spindle matrix, in controlling spindle checkpoint strength in immortal germline cells in C. elegans.

cell biology↗

Historic Genomes Uncover Demographic Shifts and Kinship Structures in Post-Roman Central Europe

Many European towns and villages trace their origins to Early Medieval foundations. In former Roman territories, their emergence has traditionally been linked to mass migrations from outside the Roman Empire. However, recent studies have emphasised local continuity with some individual-level mobility. We generated and analysed 248 historic genomes from Late Roman (3rd and 4th century CE) and Early Medieval (5th-8th century CE) burial sites in southern Germany, comparing them to over 2,500 contemporary and Iron Age genomes in addition to 1,344 modern-day genomes from Germany, Italy and Great-Britain. Despite small inferred Early Medieval period community sizes, genetic diversity exceeded that of modern German cities. In the Altheim graveyard, established in the 5th century by a group of Northern European descent, we inferred a demographic shift in the 6th century with the integration of newcomers with ancestry typical of a nearby Roman military camp, likely as a result of the collapse of Roman state structures. We reconstructed multigenerational pedigrees and, using a novel approach to infer ancestry of unsampled relatives, inferred immediate intermarriage between incoming and local groups, with a distinct tendency for men from former Roman background marrying women of northern descent. Burial proximity correlates strongly with kinship, in some cases spanning six generations. These communities were organized around small family units, exhibited loosely patrilineal or bilateral descent patterns, practiced reproductive monogamy, and avoided close-kin marriages. Such practices reflect broader transformations in family structures that began during the Late Roman period, were transferred to small agrarian societies in the Early Medieval period, and continued to shape European societies. By the 7th century, ongoing admixture had shaped genetic diversity patterns into those resembling Central Europe today.

genetics↗

Bcl-2 Oligomerizes Bax on the Mitochondrial Membrane Surface Preventing the Initial Stages of Apoptosis

The Bcl-2 family of proteins control mitochondrial outer membrane (MOM) pore formation, crucial to cellular clearance via apoptosis. However, the molecular principles by which opposing family members inhibit, mediate or promote MOM perforation remain elusive. Here, we demonstrate that cell-protecting Bcl-2 directly sequesters cell-killing Bax into a protein-protein complex at the membrane interface preventing Bax forming apoptotic pores. Neutron reflectometry showed Bax association with Bcl-2 occurs through the formation of Bax protein oligomers on the membrane surface. Bax binding to the membrane surface was proportional to the membrane-embedded Bcl-2 suggestive of protein-protein complex formation through both Bcl-2/Bax and Bax/Bax interactions. Bcl-2/Bax sequestration to prevent perforation was observed in membrane models with and without pro-apoptotic cardiolipin present. Our findings shed fundamental new light on the communication of Bcl-2 with its cell-killing relatives at the mitochondrias membraneous exterior to prevent cells from undergoing apoptosis. TeaserMembrane-embedded Bcl-2 sequesters Bax, to prevent the perforation of mitochondrial membranes by Bax which would initiate apoptosis.

biophysics↗

Microscopy Nodes: versatile 3D microscopy visualization with Blender

Effective visualization of 3D microscopy data is essential for communicating biological results. While scientific 3D rendering software is specifically designed for this purpose, it often lacks the flexibility found in non-scientific software like Blender, which is a free and open-source 3D graphics platform. However, loading microscopy data in Blender is not trivial. To bridge this gap, we introduce Microscopy Nodes, an extension for Blender that enables the seamless integration of large microscopy data. Microscopy Nodes provides efficient loading and visualization of up to 5D microscopy data from Tif and OME-Zarr files. Microscopy Nodes supports various visualization modes including volumetric, isosurface, and label-mask representations, and offers additional tools for slicing, annotation, and dynamic adjustments. By leveraging Blenders advanced rendering capabilities, users can create high-quality visualizations that accommodate both light and electron microscopy. Microscopy Nodes makes powerful, clear data visualization available to all researchers, regardless of their computational experience, and is available through the Blender extensions platform with comprehensive tutorials.

cell biology↗

SpotMAX: a generalist framework for multi-dimensional automatic spot detection and quantification

The analysis of spot-like structures is a widespread task in microscopy-based cell biology. Existing solutions are typically specific to single applications and do not use multi-dimensional information from 5D datasets. Therefore, experimental scientists often resort to subjective manual annotation. Here, we present SpotMAX, a generalist AI-driven framework for automated spot detection and quantification. SpotMAX leverages the full scope of multi-dimensional datasets with an easy-to-use interface and an embedded framework for cell segmentation and tracking. SpotMAX outperforms state-of-the-art tools, and in some cases, even expert human annotators. We applied SpotMAX across diverse experimental questions, ranging from meiotic crossover events in C. elegans to mitochondrial DNA dynamics in S. cerevisiae and telomere length in mouse stem cells, leading to new biological insights. With its flexibility in integrating AI workflows, we anticipate that SpotMAX will become the standard for spot analysis in microscopy data. Source code: https://github.com/SchmollerLab/SpotMAX

cell biology↗

The Unified Phenotype Ontology (uPheno): A framework for cross-species integrative phenomics

Phenotypic data are critical for understanding biological mechanisms and consequences of genomic variation, and are pivotal for clinical use cases such as disease diagnostics and treatment development. For over a century, vast quantities of phenotype data have been collected in many different contexts covering a variety of organisms. The emerging field of phenomics focuses on integrating and interpreting these data to inform biological hypotheses. A major impediment in phenomics is the wide range of distinct and disconnected approaches to recording the observable characteristics of an organism. Phenotype data are collected and curated using free text, single terms or combinations of terms, using multiple vocabularies, terminologies, or ontologies. Integrating these heterogeneous and often siloed data enables the application of biological knowledge both within and across species. Existing integration efforts are typically limited to mappings between pairs of terminologies; a generic knowledge representation that captures the full range of cross-species phenomics data is much needed. We have developed the Unified Phenotype Ontology (uPheno) framework, a community effort to provide an integration layer over domain-specific phenotype ontologies, as a single, unified, logical representation. uPheno comprises (1) a system for consistent computational definition of phenotype terms using ontology design patterns, maintained as a community library; (2) a hierarchical vocabulary of species-neutral phenotype terms under which their species-specific counterparts are grouped; and (3) mapping tables between species-specific ontologies. This harmonized representation supports use cases such as cross-species integration of genotype-phenotype associations from different organisms and cross-species informed variant prioritization.

bioinformatics↗

Pulsed stimulated Brillouin microscopy enables high-sensitivity mechanical imaging of live and fragile biological specimens

Brillouin microscopy is an emerging optical elastography technique capable of assessing mechanical properties of biological samples in a 3D, all-optical and hence non-contact fashion. The typically weak Brillouin scattering signal can be substantially enhanced via a stimulated photon-phonon process, which improves the signal-to-background ratio (SBR) as well as provides higher spectral resolution. However, current implementations of stimulated Brillouin spectroscopy (SBS) require high pump powers, which prohibit applications in many areas of biology, especially when studying photosensitive samples, or when live-imaging in 3D and/or over extended time periods. Here, we present a pulsed SBS scheme that takes full advantage of the non-linearity of the pump-probe interaction in SBS. In particular, we show that through quasi-pulsing and diligent optimization of signal detection parameters, the required pump laser power can be decreased ~20-fold without affecting the signal levels or spectral precision. Moreover, we devise a custom analysis approach that facilitates the analysis of complex, multi-peaked Brillouin spectra in order to harness the high spectral resolution of SBS for the specific identification of biomechanical components inside the point-spread function of the microscope. We then demonstrate the low-phototoxicity and high-specificity of our pulsed SBS approach by imaging sensitive single cells, zebrafish larvae, and mouse embryos as well as adult C. elegans with sub-cellular detail. Furthermore, our method permits observing the mechanics of organoids and C. elegans embryos over time. We expect that the substantially lower photo-burden and improved SBR of pulsed SBS will facilitate studying biomechanics in 3D at high spatio-temporal resolution in living biological specimens in a non-invasive manner, opening up exciting new possibilities for the field of mechanobiology.

bioengineering↗

Activity in perirhinal and entorhinal cortex predicts observer-specific perceived visual similarities between objects

Vision neuroscience has made great strides in understanding the hierarchical organization of object representations along the ventral visual stream (VVS). How VVS representations capture fine-grained visual similarities between objects that observers subjectively perceive has received limited examination so far. In the current study, we addressed this question by focusing on perceived visual similarities among subordinate exemplars of real world-categories. We hypothesized that these perceived similarities are reflected with highest fidelity in neural activity patterns downstream from inferotemporal regions, namely in perirhinal and anterolateral entorhinal cortex in the medial temporal-lobe. To address this issue with fMRI, we administered a modified 1-Back task that required discrimination between category exemplars as well as categorization. Further, we obtained observer-specific ratings of perceived visual similarities, which predicted behavioural performance during scanning. As anticipated, we found that activity patterns in perirhinal and anterolateral entorhinal cortex predicted the structure of perceived visual similarity relationships among category exemplars, including its observer-specific component, with higher precision than any other VVS region. Our findings provide new evidence that subjective aspects of object perception that rely on fine-grained visual differentiation are reflected with highest fidelity in the medial temporal lobe.

neuroscience↗

The influence of heart rate variability biofeedback on cardiac regulation and functional brain connectivity

BackgroundHeart rate variability (HRV) biofeedback has a beneficial impact on perceived stress and emotion regulation. However, its impact on brain function is still unclear. In this study, we aimed to investigate the effect of an 8-week HRV-biofeedback intervention on functional brain connectivity in healthy subjects. MethodsHRV biofeedback was carried out in five sessions per week, including four at home and one in our lab. A control group played jump nrun games instead of the training. Functional magnetic resonance imaging was conducted before and after the intervention in both groups. To compute resting state functional connectivity (RSFC), we defined regions of interest in the ventral medial prefrontal cortex (VMPFC) and a total of 260 independent anatomical regions for network-based analysis. Changes of RSFC of the VMPFC to other brain regions were compared between groups. Temporal changes of HRV during the resting state recording were correlated to dynamic functional connectivity of the VMPFC. ResultsFirst, we corroborated the role of the VMPFC in cardiac autonomic regulation. We found that temporal changes of HRV were correlated to dynamic changes of prefrontal connectivity, especially to the middle cingulate cortex, left anterior insula, right amygdala, supplementary motor area, dorsal and ventral lateral prefrontal regions. The biofeedback group showed a drop in heart rate by 5.5 beats/min and an increased RMSSD as a measure of HRV by 10.1ms (33%) after the intervention. Functional connectivity of the VMPFC increased mainly to the right anterior insula, the dorsal anterior cingulate cortex and the dorsolateral prefrontal cortex after biofeedback intervention when compared to changes in the control group. Network-based statistic showed that biofeedback had an influence on a broad functional network of brain regions. ConclusionOur results show that increased vagal modulation induced by HRV-biofeedback is accompanied by changes in functional brain connectivity during resting state.

neuroscience↗

The interaction of crossover formation and the dynamic architecture of the synaptonemal complex during meiosis

During meiosis, pairing between homologous chromosomes is stabilized by the assembly of a protein lattice known as the synaptonemal complex (SC). The SC ensures the formation of crossovers between homologous chromosomes and also regulates their distribution. However, how the SC regulates crossover formation remains elusive. We isolated an unusual mutation in C. elegans that disrupts crossover interference but not the assembly of the SC. This mutation alters the unique C-terminal domain of an essential SC protein, SYP-4, a likely ortholog of the vertebrate SC protein SIX6OS1. To characterize the structure of the SC in wild-type and mutant animals, we use three-dimensional STochastic Optical Reconstruction Microscopy (3D-STORM) to interrogate the molecular architecture of the SC in intact germline tissue from C. elegans. The approach enabled us to define positions of protein epitopes with respect to the 3D architecture of this complex. Using a probabilistic mapping approach to analyze super-resolution image data, we detect a marked structural transition in wild-type animals that coincides with crossover designation. We also found that our syp-4 mutant subtly perturbs SC architecture. Our findings add to growing evidence that the SC is an active material whose molecular organization contributes to chromosome-wide crossover regulation.

cell biology↗

Unfolding the hippocampus: An intrinsic coordinate system for subfield segmentations and quantitative mapping

The hippocampus, like the neocortex, has a morphological structure that is complex and variable in its folding pattern, especially in the hippocampal head. The current study presents a computational method to unfold hippocampal grey matter, with a particular focus on the hippocampal head where complexity is highest due to medial curving of the structure and the variable presence of digitations. This unfolding was performed on segmentations from high-resolution, T2-weighted 7T MRI data from 12 healthy participants and one surgical patient with epilepsy whose resected hippocampal tissue was used for histological validation. We traced a critical hippocampal component, the hippocampal sulcus and stratum radiatum, lacunosum moleculaire, (SRLM) in these images, then employed user-guided semi-automated techniques to detect and subsequently unfold the surrounding hippocampal grey matter. This unfolding was performed by solving Laplaces equation in three dimensions of interest (long-axis, proximal-distal, and laminar). The resulting unfolded coordinate space provides an intuitive way of mapping the hippocampal subfields in 2D space (long-axis and proximal-distal), such that similar borders can be applied in the head, body, and tail of the hippocampus independently of variability in folding. This unfolded coordinate space was employed to map intracortical myelin and thickness in relation to subfield borders, which revealed intracortical myelin differences that closely follow the subfield borders used here. Examination of a histological sample from a patient with epilepsy reveals that our unfolded coordinate system shows biological validity, and that subfield segmentations applied in this space are able to capture features not seen in manual tracing protocols.\n\nResearch highlightsO_LISRLM in hippocampal head consistently detected with 7T, T2 isotropic MRI\nC_LIO_LIHippocampal grey matter unfolded using Laplaces equation in 3D\nC_LIO_LIIntracortical myelin and thickness mapped in unfolded coordinate space\nC_LIO_LIUnfolded subfields capture critical structural regularities and agree with histology\nC_LI

neuroscience↗