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Understanding vibrissal transduction has advanced by serial sectioning and identified afferent recordings, but afferent mapping onto the complex, encapsulated follicle remains unclear. Here, we reveal male rat C2 vibrissa follicle innervation through synchrotron X-ray phase contrast tomograms. Morphological analysis identified 5% superficial, ~32 % unmyelinated and 63% myelinated deep vibrissal nerve axons. Myelinated afferents consist of each one third Merkel and club-like, and one sixth Ruffini-like and lanceolate endings. Unsupervised clustering of afferent properties aligns with classic morphological categories and revealed previously unrecognized club-like afferent subtypes distinct in axon diameter and Ranvier internode distance. Myelination and axon diameters indicate a proximal-to-distal axon-velocity gradient along the follicle. Axons innervate preferentially dorso-caudally to the vibrissa, presumably to sample contacts from vibrissa protraction. Afferents organize in axon-arms innervating discrete angular territories. The radial axon-arm arrangement around the vibrissa maps into a linear representation of axon-arm bands in the nerve. Such follicle linearization presumably instructs downstream linear brainstem barrelettes. Synchrotron imaging provides a synopsis of afferents and mechanotransductory machinery. The vibrissa follicle is a blood-filled encapsulated mechano-transducer, the structure of which has been difficult to resolve. Here, Gerhardt et al. reveal 3D follicle-afferents architecture and accessorial structures by synchrotron X-ray tomography.

X-ray Phase Contrast Tomography (XPCT) based on wavefield propagation has been established as a high resolution three-dimensional (3D) imaging modality, suitable to reconstruct the intricate structure of soft tissues, and the corresponding pathological alterations. However, for biomedical research, more is needed than 3D visualisation and rendering of the cytoarchitecture in a few selected cases. First, the throughput needs to be increased to cover a statistically relevant number of samples. Second, the cytoarchitecture has to be quantified in terms of morphometric parameters, independent of visual impression. Third, dimensionality reduction and classification are required for identification of effects and interpretation of results. To address these challenges, we here design and implement a novel integrated and high throughput XPCT imaging and analysis workflow for 3D histology, pathohistology and drug testing. Our approach uses semi-automated data acquisition, reconstruction and statistical quantification. We demonstrate its capability for the example of lung pathohistology in Covid-19. Using a small animal model, different Covid-19 drug candidates are administered after infection and tested in view of restoration of the physiological cytoarchitecture, specifically the alveolar morphology. To this end, we then use morphometric parameter determination followed by a dimensionality reduction and classification based on optimal transport. This approach allows efficient discrimination between physiological and pathological lung structure, thereby providing quantitative insights into the pathological progression and partial recovery due to drug treatment. Finally, we stress that the XPCT image chain implemented here only used synchrotron radiation for validation, while the data used for analysis was recorded with laboratory μ CT radiation, more easily accessible for pre-clinical research.

The following case report details the case of a 40-year-old Caucasian patient who presented with dyspnea following a serologically confirmed mild-to-severe pulmonary infection with SARS-CoV-2. Chest computer tomography revealed a solitary ground-glass pulmonary nodule in the lower right lobe, measuring 2.1 cm in diameter. Video-assisted thoracoscopic surgery wedge resection revealed well-circumscribed lymphoid aggregates adjacent to the round, smaller airways, bronchioles, and blood vessels. IgKappa B exhibited a monoclonal polyclonal pattern, in contrast to the behavior exhibited by IgKappa A and IgLambda. In the following discussion, the lymphoid lesion was considered in the context of lymphoid hyperplasia, accompanied by an early infiltration of low-grade extranodal B cell lymphoma of the bronchus-associated lymphoid tissue (BALToma).

Three-dimensional (3D) imaging is crucial for elucidating the complex structure of organoid models which involve complex spatial cellular and tissue organization in 3D. While a variety of volume imaging methods, including novel light microscopy tools, are now well established to probe the cellular complexity of organoids in 3D, the gold standard for obtaining a precise morphological picture is histology, a traditionally 2D imaging technique that relies on slicing the specimen and therefore has severe limitations in scalability and volumetric imaging. X-ray phase-contrast tomography (XPCT) has emerged as an imaging modality capable of extending conventional histology into the third dimension. While it has been applied to various types of animal and human tissues, its applicability to organoid systems, however, is yet in its infancy. Here, we use XPCT for 3D histology of unstained and formalin-fixed paraffin-embedded human heart-forming organoids (HFOs) at multiple scales and with isotropic resolution. Derived from human pluripotent stem cells, HFOs are a complex and highly structured in vitro model of early heart, foregut and vasculature development, resembling the early human heart-forming region. Using highly coherent synchrotron radiation, we show that HFOs and their different tissue elements can be visualized in their full three-dimensionality and at subcellular scale. The intricate structure of human heart-forming organoids, including their various tissue components and vascularization, is studied in its three-dimensionality and at the subcellular level using multiscale X-ray phase-contrast tomography.

Phase-contrast X-ray lung imaging has broken new ground in preclinical respiratory research by improving contrast at air/tissue interfaces. To minimize blur from respiratory motion, intubation and mechanical ventilation is commonly employed for end-inspiration gated imaging at synchrotrons and in the laboratory. Inevitably, the prospect of ventilation induced lung injury (VILI) renders mechanical ventilation a confounding factor in respiratory studies of animal models. Here we demonstrate proof-of-principle 3D imaging of the tracheobronchial tree in free-breathing mice without mechanical ventilation at radiation levels compatible with longitudinal studies. We use a prospective gating approach for end-expiration propagation-based phase-contrast X-ray imaging where the natural breathing of the mouse dictates the acquisition flow. We achieve intrapulmonary spatial resolution in the 30-μm-range, sufficient for resolving terminal bronchioles in the 60-μm-range distinguished from the surrounding lung parenchyma. These results should enable non-invasive longitudinal studies of native state murine airways for translational lung disease research in the laboratory. Mechanical ventilation of living animals is routinely used to achieve high-resolution pulmonary imaging, but this can damage the subject. Here, an alternative, free-breathing method enables X-ray tomography with 30 μm resolution.

The vibrissa follicle is a complex mechanotransducer with intricate accessory structures such as vibrissa, ring sinus and ringwulst as well as rich innervation by diverse afferent types. Establishing how afferent types and accessory structures operate together to derive specific kinds of sensory information has been challenging, because we often lack precise information on afferent types, accessory structures and vibrissa function. Here we address this challenge by synchrotron X-ray imaging of vibrissa follicles of rat vibrissae with distinct function. Specifically, we characterize accessory structures and trace myelinated axons of the all-purpose-sensing C2-, an object-sensing micro-, the wind-sensing supraorbital- and the ground-sensing trident-vibrissa. We find that while vibrissa length and follicle size differ widely across these vibrissae, the ringwulst and the associated club-like afferents are of near constant diameter and height and appear to form a non-scalable sensory module. The two longer vibrissae (supraorbital and C2 vibrissa) have noticeably more club like afferents, suggesting a special role of the ringwulst in transducing presumably smaller deflection angles encountered by long sensory hairs. The trident vibrissa receives overall few afferents, which are strongly polarized to the posterior vibrissa-shaft, a putative specialization to sensing forward-egomotion. We conclude that high-resolution structural analysis allows relating follicle architecture and function. Structure-function relationship of the vibrissa follicle and associated afferents are revealed by synchrotron X-ray imaging of rat vibrissae with distinct functions.

This study leverages x‐ray phase‐contrast tomography (XPCT) for detailed analysis of neurodegenerative diseases, focusing on the three‐dimensional (3D) visualization and quantification of neuropathological features within fixed human postmortem tissue. XPCT with synchrotron radiation offers micrometer and even sub‐micron resolution, enabling us to examine intra‐ and extraneuronal aggregates and inclusions such as Lewy bodies (LBs), granulovacuolar degeneration (GvD), Hirano bodies (HBs), neurofibrillary tangles (NFTs), β‐amyloid plaques, and vascular amyloid deposits in three dimensions. In the reconstructions, we identified the highest electron densities in Hirano and LBs, while NFTs exhibited no significant increase in XPCT contrast. Using cutting‐edge high‐resolution x‐ray synchrotron beamlines, we were now able to detect even detect subcellular differences in electron densities found in GvD. Small‐scale inhomogeneities of the electron density were also detected in LBs, potentially relating to inclusions of organelles. Additionally, we reveal here a peculiar 3D geometry of HBs and demonstrate the co‐occurrence with GvD in the same neuron. These findings underscore the potential of XPCT as a powerful, label‐free tool for spatially resolved neuropathological investigations, opening new avenues for the systematic 3D characterization of inclusions and aggregates in neurodegeneration.

The human placenta exhibits a complex three-dimensional (3D) structure with a interpenetrating vascular tree and large internal interfacial area. In a unique and yet insufficiently explored way, this parenchymal structure enables its multiple functions as a respiratory, renal, and gastrointestinal multiorgan. The histopathological states are highly correlated with complications and health issues of mother, and fetus or newborn. Macroscopic and microscopic examination has so far been challenging to reconcile on the entire organ. Here we show that anatomical and histological scales can be bridged with the advent of hierarchical phase-contrast tomography and highly brilliant synchrotron radiation. To this end, we are exploiting the new capabilities offered by the BM18 beamline at ESRF, Grenoble for whole organ as well as the coherence beamline P10 at DESY, Hamburg for high-resolution, creating unique multiscale datasets. We also show that within certain limits, translation to μCT instrumentation for 3D placenta examination becomes possible based on advanced preparation and CT protocols, while segmentation of the datasets by machine learning now remains the biggest challenge.

X-ray Phase Contrast Tomography (XPCT) based on wavefield propagation has been established as a high resolution three-dimensional (3D) imaging modality, suitable to reconstruct the intricate structure of soft tissues, and the corresponding pathological alterations. However, for biomedical research, more is needed than 3D visualisation and rendering of the cytoarchitecture in a few selected cases. First, the throughput needs to be increased to cover a statistically relevant number of samples. Second, the cytoarchitecture has to be quantified in terms of morphometric parameters, independent of visual impression. Third, dimensionality reduction and classification are required for identification of effects and interpretation of results. In this work, we present a workflow implemented at a laboratory μCT setup, using semi-automated data acquisition, reconstruction and statistical quantification of lung tissue in an early screen of Covid-19 drug candidates. Different drugs were tested in a hamster model after SARS-CoV-2 infection. To make full use of the recorded high-throughput XPCT data, we then used morphometric parameter determination followed by a dimensionality reduction and classification based on optimal transport. This approach allows efficient discrimination between physiological and pathological lung structure, thereby providing invaluable insights into the pathological progression and partial recovery due to drug treatment.Competing Interest StatementThe authors have declared no competing interest.

Elephants have elaborate trunk skills and large, but poorly understood brains. Here we study trunk representations in elephant trigeminal nuclei, which form large protrusions on the ventral brainstem. Dense vascularization and intense cytochrome-oxidase reactivity distinguish several elongated putative trunk modules, which repeat in the anterior-posterior direction; our analysis focuses on the most anterior and largest of the units, the putative nucleus principalis trunk module. Module neuron density is low and glia outnumbers neurons by ~108:1. Dendritic trees are elongated along the axis of axon bundles (myelin stripes) transversing the trunk module. Furthermore, synchrotron X-ray phase contrast tomography suggests myelin-stripe-axons transverse the trunk module. We show a remarkable correspondence of trunk module myelin stripes and trunk folds. Myelin stripes show little relation to trigeminal neurons and stripe-axons appear to often go nowhere; these observations suggest to the possibility that myelin-stripes might serve to separate trunk-fold domains rather than to connect neurons. The myelin-stripes-to-folds mapping allowed to determine neural magnification factors, which changed from 1000:1 proximally to 5:1 in the trunk finger. Asian elephants have fewer (640,000) trunk-module neurons than Africans (740,000) and show enlarged representations of trunk parts involved in object wrapping. We conclude the elephant trigeminal trunk module is exquisitely organized into trunk-fold-related units.Competing Interest StatementThe authors have declared no competing interest.