High-throughput classification of S. cerevisiae tetrads using deep learning.

Meiotic crossovers play a vital role in proper chromosome segregation and evolution of most sexually reproducing organisms. Meiotic recombination can be visually observed in Saccharomyces cerevisiae tetrads using linked spore-autonomous fluorescent markers placed at defined intervals within the genome, which allows for analysis of meiotic segregation without the need for tetrad dissection. To automate the analysis, we developed a deep learning-based image recognition and classification pipeline for high-throughput tetrad detection and meiotic crossover classification. As a proof of concept, we analyzed a large image data set from wild-type and selected gene knock-out mutants to quantify crossover frequency, interference, chromosome missegregation, and gene conversion events. The deep learning-based method has the potential to accelerate the discovery of new genes involved in meiotic recombination in S. cerevisiae such as the underlying factors controlling crossover frequency and interference.

Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS.

Loss of connectivity between spinal V1 inhibitory interneurons and motor neurons is found early in disease in the SOD1G93A mice. Such changes in premotor inputs can contribute to homeostatic imbalance of motor neurons. Here, we show that the Extended Synaptotagmin 1 (Esyt1) presynaptic organizer is downregulated in V1 interneurons. V1 restricted overexpression of Esyt1 rescues inhibitory synapses, increases motor neuron survival, and ameliorates motor phenotypes. Two gene therapy approaches overexpressing ESYT1 were investigated; one for local intraspinal delivery, and the other for systemic administration using an AAV-PHP.eB vector delivered intravenously. Improvement of motor functions is observed in both approaches, however systemic administration appears to significantly reduce onset of motor impairment in the SOD1G93A mice in absence of side effects. Altogether, we show that stabilization of V1 synapses by ESYT1 overexpression has the potential to improve motor functions in ALS, demonstrating that interneurons can be a target to attenuate ALS symptoms.

Spinal inhibitory neurons degenerate before motor neurons and excitatory neurons in a mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of somatic motor neurons. A major focus has been directed to motor neuron intrinsic properties as a cause for degeneration, while less attention has been given to the contribution of spinal interneurons. In the present work, we applied multiplexing detection of transcripts and machine learning-based image analysis to investigate the fate of multiple spinal interneuron populations during ALS progression in the SOD1G93A mouse model. The analysis showed that spinal inhibitory interneurons are affected early in the disease, before motor neuron death, and are characterized by a slow progressive degeneration, while excitatory interneurons are affected later with a steep progression. Moreover, we report differential vulnerability within inhibitory and excitatory subpopulations. Our study reveals a strong interneuron involvement in ALS development with interneuron specific degeneration. These observations point to differential involvement of diverse spinal neuronal circuits that eventually may be determining motor neuron degeneration.

Machine learning for analysis of experimental scattering and spectroscopy data in materials chemistry.

The rapid growth of materials chemistry data, driven by advancements in large-scale radiation facilities as well as laboratory instruments, has outpaced conventional data analysis and modelling methods, which can require enormous manual effort. To address this bottleneck, we investigate the application of supervised and unsupervised machine learning (ML) techniques for scattering and spectroscopy data analysis in materials chemistry research. Our perspective focuses on ML applications in powder diffraction (PD), pair distribution function (PDF), small-angle scattering (SAS), inelastic neutron scattering (INS), and X-ray absorption spectroscopy (XAS) data, but the lessons that we learn are generally applicable across materials chemistry. We review the ability of ML to identify physical and structural models and extract information efficiently and accurately from experimental data. Furthermore, we discuss the challenges associated with supervised ML and highlight how unsupervised ML can mitigate these limitations, thus enhancing experimental materials chemistry data analysis. Our perspective emphasises the transformative potential of ML in materials chemistry characterisation and identifies promising directions for future applications. The perspective aims to guide newcomers to ML-based experimental data analysis.

Pedunculopontine Chx10+ neurons control global motor arrest in mice.

Arrest of ongoing movements is an integral part of executing motor programs. Behavioral arrest may happen upon termination of a variety of goal-directed movements or as a global motor arrest either in the context of fear or in response to salient environmental cues. The neuronal circuits that bridge with the executive motor circuits to implement a global motor arrest are poorly understood. We report the discovery that the activation of glutamatergic Chx10-derived neurons in the pedunculopontine nucleus (PPN) in mice arrests all ongoing movements while simultaneously causing apnea and bradycardia. This global motor arrest has a pause-and-play pattern with an instantaneous interruption of movement followed by a short-latency continuation from where it was paused. Mice naturally perform arrest bouts with the same combination of motor and autonomic features. The Chx10-PPN-evoked arrest is different to ventrolateral periaqueductal gray-induced freezing. Our study defines a motor command that induces a global motor arrest, which may be recruited in response to salient environmental cues to allow for a preparatory or arousal state, and identifies a locomotor-opposing role for rostrally biased glutamatergic neurons in the PPN.

DeepStruc: towards structure solution from pair distribution function data using deep generative models.

Structure solution of nanostructured materials that have limited long-range order remains a bottleneck in materials development. We present a deep learning algorithm, DeepStruc, that can solve a simple monometallic nanoparticle structure directly from a Pair Distribution Function (PDF) obtained from total scattering data by using a conditional variational autoencoder. We first apply DeepStruc to PDFs from seven different structure types of monometallic nanoparticles, and show that structures can be solved from both simulated and experimental PDFs, including PDFs from nanoparticles that are not present in the training distribution. We also apply DeepStruc to a system of hcp, fcc and stacking faulted nanoparticles, where DeepStruc recognizes stacking faulted nanoparticles as an interpolation between hcp and fcc nanoparticles and is able to solve stacking faulted structures from PDFs. Our findings suggests that DeepStruc is a step towards a general approach for structure solution of nanomaterials.

Automatic airway segmentation from computed tomography using robust and efficient 3-D convolutional neural networks.

This paper presents a fully automatic and end-to-end optimised airway segmentation method for thoracic computed tomography, based on the U-Net architecture. We use a simple and low-memory 3D U-Net as backbone, which allows the method to process large 3D image patches, often comprising full lungs, in a single pass through the network. This makes the method simple, robust and efficient. We validated the proposed method on three datasets with very different characteristics and various airway abnormalities: (1) a dataset of pediatric patients including subjects with cystic fibrosis, (2) a subset of the Danish Lung Cancer Screening Trial, including subjects with chronic obstructive pulmonary disease, and (3) the EXACT'09 public dataset. We compared our method with other state-of-the-art airway segmentation methods, including relevant learning-based methods in the literature evaluated on the EXACT'09 data. We show that our method can extract highly complete airway trees with few false positive errors, on scans from both healthy and diseased subjects, and also that the method generalizes well across different datasets. On the EXACT'09 test set, our method achieved the second highest sensitivity score among all methods that reported good specificity.

Locomotor deficits in a mouse model of ALS are paralleled by loss of V1-interneuron connections onto fast motor neurons.

ALS is characterized by progressive inability to execute movements. Motor neurons innervating fast-twitch muscle-fibers preferentially degenerate. The reason for this differential vulnerability and its consequences on motor output is not known. Here, we uncover that fast motor neurons receive stronger inhibitory synaptic inputs than slow motor neurons, and disease progression in the SOD1G93A mouse model leads to specific loss of inhibitory synapses onto fast motor neurons. Inhibitory V1 interneurons show similar innervation pattern and loss of synapses. Moreover, from postnatal day 63, there is a loss of V1 interneurons in the SOD1G93A mouse. The V1 interneuron degeneration appears before motor neuron death and is paralleled by the development of a specific locomotor deficit affecting speed and limb coordination. This distinct ALS-induced locomotor deficit is phenocopied in wild-type mice but not in SOD1G93A mice after appearing of the locomotor phenotype when V1 spinal interneurons are silenced. Our study identifies a potential source of non-autonomous motor neuronal vulnerability in ALS and links ALS-induced changes in locomotor phenotype to inhibitory V1-interneurons.

Developing and validating COVID-19 adverse outcome risk prediction models from a bi-national European cohort of 5594 patients.

Patients with severe COVID-19 have overwhelmed healthcare systems worldwide. We hypothesized that machine learning (ML) models could be used to predict risks at different stages of management and thereby provide insights into drivers and prognostic markers of disease progression and death. From a cohort of approx. 2.6 million citizens in Denmark, SARS-CoV-2 PCR tests were performed on subjects suspected for COVID-19 disease; 3944 cases had at least one positive test and were subjected to further analysis. SARS-CoV-2 positive cases from the United Kingdom Biobank was used for external validation. The ML models predicted the risk of death (Receiver Operation Characteristics-Area Under the Curve, ROC-AUC) of 0.906 at diagnosis, 0.818, at hospital admission and 0.721 at Intensive Care Unit (ICU) admission. Similar metrics were achieved for predicted risks of hospital and ICU admission and use of mechanical ventilation. Common risk factors, included age, body mass index and hypertension, although the top risk features shifted towards markers of shock and organ dysfunction in ICU patients. The external validation indicated fair predictive performance for mortality prediction, but suboptimal performance for predicting ICU admission. ML may be used to identify drivers of progression to more severe disease and for prognostication patients in patients with COVID-19. We provide access to an online risk calculator based on these findings.

Graph refinement based airway extraction using mean-field networks and graph neural networks.

Graph refinement, or the task of obtaining subgraphs of interest from over-complete graphs, can have many varied applications. In this work, we extract trees or collection of sub-trees from image data by, first deriving a graph-based representation of the volumetric data and then, posing the tree extraction as a graph refinement task. We present two methods to perform graph refinement. First, we use mean-field approximation (MFA) to approximate the posterior density over the subgraphs from which the optimal subgraph of interest can be estimated. Mean field networks (MFNs) are used for inference based on the interpretation that iterations of MFA can be seen as feed-forward operations in a neural network. This allows us to learn the model parameters using gradient descent. Second, we present a supervised learning approach using graph neural networks (GNNs) which can be seen as generalisations of MFNs. Subgraphs are obtained by training a GNN-based graph refinement model to directly predict edge probabilities. We discuss connections between the two classes of methods and compare them for the task of extracting airways from 3D, low-dose, chest CT data. We show that both the MFN and GNN models show significant improvement when compared to one baseline method, that is similar to a top performing method in the EXACT'09 Challenge, and a 3D U-Net based airway segmentation model, in detecting more branches with fewer false positives.

Segmentation of roots in soil with U-Net.

BACKGROUND: Plant root research can provide a way to attain stress-tolerant crops that produce greater yield in a diverse array of conditions. Phenotyping roots in soil is often challenging due to the roots being difficult to access and the use of time consuming manual methods. Rhizotrons allow visual inspection of root growth through transparent surfaces. Agronomists currently manually label photographs of roots obtained from rhizotrons using a line-intersect method to obtain root length density and rooting depth measurements which are essential for their experiments. We investigate the effectiveness of an automated image segmentation method based on the U-Net Convolutional Neural Network (CNN) architecture to enable such measurements. We design a data-set of 50 annotated chicory (Cichorium intybus L.) root images which we use to train, validate and test the system and compare against a baseline built using the Frangi vesselness filter. We obtain metrics using manual annotations and line-intersect counts. RESULTS: Our results on the held out data show our proposed automated segmentation system to be a viable solution for detecting and quantifying roots. We evaluate our system using 867 images for which we have obtained line-intersect counts, attaining a Spearman rank correlation of 0.9748 and an r 2 of 0.9217. We also achieve an F 1 of 0.7 when comparing the automated segmentation to the manual annotations, with our automated segmentation system producing segmentations with higher quality than the manual annotations for large portions of the image. CONCLUSION: We have demonstrated the feasibility of a U-Net based CNN system for segmenting images of roots in soil and for replacing the manual line-intersect method. The success of our approach is also a demonstration of the feasibility of deep learning in practice for small research groups needing to create their own custom labelled dataset from scratch.

Extracting tree structures in CT data by tracking multiple statistically ranked hypotheses.

PURPOSE: In this work, we adapt a method based on multiple hypothesis tracking (MHT) that has been shown to give state-of-the-art vessel segmentation results in interactive settings, for the purpose of extracting trees. METHODS: Regularly spaced tubular templates are fit to image data forming local hypotheses. These local hypotheses are then used to construct the MHT tree, which is then traversed to make segmentation decisions. Some critical parameters in the method, we base ours on, are scale-dependent and have an adverse effect when tracking structures of varying dimensions. We propose to use statistical ranking of local hypotheses in constructing the MHT tree which yields a probabilistic interpretation of scores across scales and helps alleviate the scale dependence of MHT parameters. This enables our method to track trees starting from a single seed point. RESULTS: The proposed method is evaluated on chest computed tomography data to extract airway trees and coronary arteries and compared to relevant baselines. In both cases, we show that our method performs significantly better than the Original MHT method in semiautomatic setting. CONCLUSIONS: The statistical ranking of local hypotheses introduced allows the MHT method to be used in noninteractive settings yielding competitive results for segmenting tree structures.

Increasing Accuracy of Optimal Surfaces Using Min-Marginal Energies.

Optimal surface methods are a class of graph cut methods posing surface estimation as an n-ary ordered labeling problem. They are used in medical imaging to find interacting and layered surfaces optimally and in low order polynomial time. Representing continuous surfaces with discrete sets of labels, however, leads to discretization errors and, if graph representations are made dense, excessive memory usage. Limiting memory usage and computation time of graph cut methods are important and graphs that locally adapt to the problem has been proposed as a solution. Min-marginal energies computed using dynamic graph cuts offer a way to estimate solution uncertainty and these uncertainties have been used to decide where graphs should be adapted. Adaptive graphs, however, introduce extra parameters, complexity, and heuristics. We propose a way to use min-marginal energies to estimate continuous solution labels that does not introduce extra parameters and show empirically on synthetic and medical imaging datasets that it leads to improved accuracy. The increase in accuracy was consistent and in many cases comparable with accuracy otherwise obtained with graphs up to eight times denser, but with proportionally less memory usage and improvements in computation time.