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Light-sheet fluorescence microscopy (LSFM) is a cutting-edge volumetric imaging technique that allows for three-dimensional imaging of mesoscopic samples with decoupled illumination and detection paths. Although the selective excitation scheme of such a microscope provides intrinsic optical sectioning that minimizes out-of-focus fluorescence background and sample photodamage, it is prone to light absorption and scattering effects, which results in uneven illumination and striping artifacts in the images adversely. To tackle this issue, in this paper, we propose a blind stripe artifact removal algorithm in LSFM, called DeStripe, which combines a self-supervised spatio-spectral graph neural network with unfolded Hessian prior. Specifically, inspired by the desirable properties of Fourier transform in condensing striping information into isolated values in the frequency domain, DeStripe firstly localizes the potentially corrupted Fourier coefficients by exploiting the structural difference between unidirectional stripe artifacts and more isotropic foreground images. Affected Fourier coefficients can then be fed into a graph neural network for recovery, with a Hessian regularization unrolled to further ensure structures in the standard image space are well preserved. Since in realistic, stripe-free LSFM barely exists with a standard image acquisition protocol, DeStripe is equipped with a Self2Self denoising loss term, enabling artifact elimination without access to stripe-free ground truth images. Competitive experimental results demonstrate the efficacy of DeStripe in recovering corrupted biomarkers in LSFM with both synthetic and real stripe artifacts., Comment: Accepted by 25th International Conference on Medical Image Computing and Computer Assisted Intervention

Deep learning based classification of biomedical images requires expensive manual annotation by experts. Incomplete-supervision approaches including active learning, pre-training, and semi-supervised learning have thus been developed to increase classification performance with a limited number of annotated images. In practice, a combination of these approaches is often used to reach the desired performance for biomedical images. Most of these approaches are designed for natural images, which differ fundamentally from biomedical images in terms of color, contrast, image complexity, and class imbalance. In addition, it is not always clear which combination to use in practical cases. We, therefore, analyzed the performance of combining seven active learning, three pre-training, and two semi-supervised methods on four exemplary biomedical image datasets covering various imaging modalities and resolutions. The results showed that the ImageNet (pre-training) in combination with pseudo-labeling (semi-supervised learning) dominates the best performing combinations, while no particular active learning algorithm prevailed. For three out of four datasets, this combination reached over 90% of the fully supervised results by only adding 25% of labeled data. An ablation study also showed that pre-training and semi-supervised learning contributed up to 25% increase in F1-score in each cycle. In contrast, active learning contributed less than 5% increase in each cycle. Based on these results, we suggest employing the correct combination of pre-training and semi-supervised learning can be more efficient than active learning for biomedical image classification with limited annotated images. We believe that our study is an important step towards annotation-efficient model training for biomedical classification challenges.

Reconstructing 3D objects from 2D images is both challenging for our brains and machine learning algorithms. To support this spatial reasoning task, contextual information about the overall shape of an object is critical. However, such information is not captured by established loss terms (e.g. Dice loss). We propose to complement geometrical shape information by including multi-scale topological features, such as connected components, cycles, and voids, in the reconstruction loss. Our method uses cubical complexes to calculate topological features of 3D volume data and employs an optimal transport distance to guide the reconstruction process. This topology-aware loss is fully differentiable, computationally efficient, and can be added to any neural network. We demonstrate the utility of our loss by incorporating it into SHAPR, a model for predicting the 3D cell shape of individual cells based on 2D microscopy images. Using a hybrid loss that leverages both geometrical and topological information of single objects to assess their shape, we find that topological information substantially improves the quality of reconstructions, thus highlighting its ability to extract more relevant features from image datasets.

© 2020 Australian College of Midwives The rate of late gestation stillbirth in Australia is unacceptably high. Up to one third of stillbirths are preventable, particularly beyond 28 weeks’ gestation. The aim of this second paper in the Stillbirth in Australia series is to highlight one key national initiative, the Safer Baby Bundle (SBB), which has been led by the Centre of Research Excellence in Stillbirth in partnership with state health departments. Addressing commonly identified evidence practice gaps, the SBB contains five elements that, when implemented together, should result in better outcomes than if performed individually. This paper describes the development of the SBB, what the initiative aims to achieve, and progress to date. By collaborating with Departments of Health and other partners to amplify uptake of the SBB, we anticipate a reduction of at least 20% in Australia's stillbirth rate after 28 weeks’ gestation is achievable.

The regulation of quiescence and cell cycle entry is pivotal for the maintenance of stem cell populations. Regulatory mechanisms however are poorly understood. In particular it is unclear how the activity of single stem cells is coordinated within the population, or if cells divide in a purely random fashion. We addressed this issue by analyzing division events in an adult neural stem cell (NSC) population of the zebrafish telencephalon. Spatial statistics and mathematical modeling of over 80,000 NSCs in 36 brains revealed weakly aggregated, non-random division patterns in space and time. Analyzing divisions at two timepoints allowed us to infer cell cycle and S-phase lengths computationally. Interestingly, we observed rapid cell cycle re-entries in roughly 15% of newly born NSCs. In agent based simulations of NSC populations, this re-dividing activity sufficed to induce aggregated spatio-temporal division patterns that matched the ones observed experimentally. In contrast, omitting re-divisions lead to a random spatio-temporal distribution of dividing cells. Spatio-temporal aggregation of dividing stem cells can thus emerge from the cell’s history, regardless of possible feedback mechanisms in the population.

An intricate link is becoming apparent between metabolism and cellular identities. Here, we explore the basis for such a link in an in vitro model for early mouse embryonic development: from naive pluripotency to the specification of primordial germ cells (PGCs). Using single-cell RNA-seq with statistical modelling and modulation of energy metabolism, we demonstrate a functional role for oxidative mitochondrial metabolism in naive pluripotency. We link mitochondrial tricarboxylic acid cycle activity to IDH2-mediated production of alpha-ketoglutarate and through it, the activity of key epigenetic regulators. Accordingly, this metabolite has a role in the maintenance of naive pluripotency as well as in PGC differentiation, likely through preserving a particular histone methylation status underlying the transient state of developmental competence for the PGC fate. We reveal a link between energy metabolism and epigenetic control of cell state transitions during a developmental trajectory towards germ cell specification, and establish a paradigm for stabilizing fleeting cellular states through metabolic modulation.

Proliferating stem cells in the adult body are the source of constant regeneration. In the brain, neural stem cells (NSCs) divide to maintain the stem cell population and generate neural progenitor cells that eventually replenish mature neurons and glial cells. How much spatial coordination of NSC division and differentiation is present in a functional brain is an open question. To quantify the patterns of stem cell divisions, one has to (i) identify the pool of NSCs that have the ability to divide, (ii) determine NSCs that divide within a given time window, and (iii) analyze the degree of spatial coordination. Here, we present a bioimage informatics pipeline that automatically identifies GFP expressing NSCs in three‐dimensional image stacks of zebrafish brain from whole‐mount preparations. We exploit the fact that NSCs in the zebrafish hemispheres are located on a two‐dimensional surface and identify between 1,500 and 2,500 NSCs in six brain hemispheres. We then determine the position of dividing NSCs in the hemisphere by EdU incorporation into cells undergoing S‐phase and calculate all pairwise NSC distances with three alternative metrics. Finally, we fit a probabilistic model to the observed spatial patterns that accounts for the non‐homogeneous distribution of NSCs. We find a weak positive coordination between dividing NSCs irrespective of the metric and conclude that neither strong inhibitory nor strong attractive signals drive NSC divisions in the adult zebrafish brain. © 2017 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC.

Trees representing hierarchical knowledge are prevalent in biology and medicine. Some examples are phylogenetic trees, the hierarchical structure of biological tissues and cell lines. The increasing throughput of techniques generating such trees poses new challenges to the analysis of tree ensembles. Some typical tasks include the determination of common patterns of lineage decisions in cellular differentiation trees. Partitioning the dataset is crucial for further analysis of the cellular genealogies. In this work, we develop a method to cluster labeled binary tree structures. Furthermore, for every cluster our method selects a centroid tree that captures the characteristic mitosis patterns of the group. We evaluate this technique on synthetic data and apply it to experimental trees that embody the lineages of differentiating cells under specific conditions over time. The results of the cell lineage trees are thoroughly interpreted with expert domain knowledge.