Daily Papers

PROTACs are a promising therapeutic modality that harnesses the cell's built-in degradation machinery to degrade specific proteins. Despite their potential, developing new PROTACs is challenging and requires significant domain expertise, time, and cost. Meanwhile, machine learning has transformed drug design and development. In this work, we present a strategy for curating open-source PROTAC data and an open-source deep learning tool for predicting the degradation activity of novel PROTAC molecules. The curated dataset incorporates important information such as pDC_{50}, D_{max}, E3 ligase type, POI amino acid sequence, and experimental cell type. Our model architecture leverages learned embeddings from pretrained machine learning models, in particular for encoding protein sequences and cell type information. We assessed the quality of the curated data and the generalization ability of our model architecture against new PROTACs and targets via three tailored studies, which we recommend other researchers to use in evaluating their degradation activity models. In each study, three models predict protein degradation in a majority vote setting, reaching a top test accuracy of 82.6% and 0.848 ROC AUC, and a test accuracy of 61% and 0.615 ROC AUC when generalizing to novel protein targets. Our results are not only comparable to state-of-the-art models for protein degradation prediction, but also part of an open-source implementation which is easily reproducible and less computationally complex than existing approaches.

Identifying cell types and understanding their functional properties is crucial for unraveling the mechanisms underlying perception and cognition. In the retina, functional types can be identified by carefully selected stimuli, but this requires expert domain knowledge and biases the procedure towards previously known cell types. In the visual cortex, it is still unknown what functional types exist and how to identify them. Thus, for unbiased identification of the functional cell types in retina and visual cortex, new approaches are needed. Here we propose an optimization-based clustering approach using deep predictive models to obtain functional clusters of neurons using Most Discriminative Stimuli (MDS). Our approach alternates between stimulus optimization with cluster reassignment akin to an expectation-maximization algorithm. The algorithm recovers functional clusters in mouse retina, marmoset retina and macaque visual area V4. This demonstrates that our approach can successfully find discriminative stimuli across species, stages of the visual system and recording techniques. The resulting most discriminative stimuli can be used to assign functional cell types fast and on the fly, without the need to train complex predictive models or show a large natural scene dataset, paving the way for experiments that were previously limited by experimental time. Crucially, MDS are interpretable: they visualize the distinctive stimulus patterns that most unambiguously identify a specific type of neuron.

High-throughput screening techniques are commonly used to obtain large quantities of data in many fields of biology. It is well known that artifacts arising from variability in the technical execution of different experimental batches within such screens confound these observations and can lead to invalid biological conclusions. It is therefore necessary to account for these batch effects when analyzing outcomes. In this paper we describe RxRx1, a biological dataset designed specifically for the systematic study of batch effect correction methods. The dataset consists of 125,510 high-resolution fluorescence microscopy images of human cells under 1,138 genetic perturbations in 51 experimental batches across 4 cell types. Visual inspection of the images alone clearly demonstrates significant batch effects. We propose a classification task designed to evaluate the effectiveness of experimental batch correction methods on these images and examine the performance of a number of correction methods on this task. Our goal in releasing RxRx1 is to encourage the development of effective experimental batch correction methods that generalize well to unseen experimental batches. The dataset can be downloaded at https://rxrx.ai.

Introduction: The scientific publishing landscape is expanding rapidly, creating challenges for researchers to stay up-to-date with the evolution of the literature. Natural Language Processing (NLP) has emerged as a potent approach to automating knowledge extraction from this vast amount of publications and preprints. Tasks such as Named-Entity Recognition (NER) and Named-Entity Linking (NEL), in conjunction with context-dependent semantic interpretation, offer promising and complementary approaches to extracting structured information and revealing key concepts. Results: We present the SourceData-NLP dataset produced through the routine curation of papers during the publication process. A unique feature of this dataset is its emphasis on the annotation of bioentities in figure legends. We annotate eight classes of biomedical entities (small molecules, gene products, subcellular components, cell lines, cell types, tissues, organisms, and diseases), their role in the experimental design, and the nature of the experimental method as an additional class. SourceData-NLP contains more than 620,000 annotated biomedical entities, curated from 18,689 figures in 3,223 papers in molecular and cell biology. We illustrate the dataset's usefulness by assessing BioLinkBERT and PubmedBERT, two transformers-based models, fine-tuned on the SourceData-NLP dataset for NER. We also introduce a novel context-dependent semantic task that infers whether an entity is the target of a controlled intervention or the object of measurement. Conclusions: SourceData-NLP's scale highlights the value of integrating curation into publishing. Models trained with SourceData-NLP will furthermore enable the development of tools able to extract causal hypotheses from the literature and assemble them into knowledge graphs.

Image-based or morphological profiling is a rapidly expanding field wherein cells are "profiled" by extracting hundreds to thousands of unbiased, quantitative features from images of cells that have been perturbed by genetic or chemical perturbations. The Cell Painting assay is the most popular imaged-based profiling assay wherein six small-molecule dyes label eight cellular compartments and thousands of measurements are made, describing quantitative traits such as size, shape, intensity, and texture within the nucleus, cytoplasm, and whole cell (Cimini et al., 2023). We have created the Cell Painting Gallery, a publicly available collection of Cell Painting datasets, with granular dataset descriptions and access instructions. It is hosted by AWS on the Registry of Open Data (RODA). As of January 2024, the Cell Painting Gallery holds 656 terabytes (TB) of image and associated numerical data. It includes the largest publicly available Cell Painting dataset, in terms of perturbations tested (Joint Undertaking for Morphological Profiling or JUMP (Chandrasekaran et al., 2023)), along with many other canonical datasets using Cell Painting, close derivatives of Cell Painting (such as LipocyteProfiler (Laber et al., 2023) and Pooled Cell Painting (Ramezani et al., 2023)).

Over the past decade, the revolution in single-cell sequencing has enabled the simultaneous molecular profiling of various modalities across thousands of individual cells, allowing scientists to investigate the diverse functions of complex tissues and uncover underlying disease mechanisms. Among all the analytical steps, assigning individual cells to specific types is fundamental for understanding cellular heterogeneity. However, this process is usually labor-intensive and requires extensive expert knowledge. Recent advances in large language models (LLMs) have demonstrated their ability to efficiently process and synthesize vast corpora of text to automatically extract essential biological knowledge, such as marker genes, potentially promoting more efficient and automated cell type annotations. To thoroughly evaluate the capability of modern instruction-tuned LLMs in automating the cell type identification process, we introduce SOAR, a comprehensive benchmarking study of LLMs for cell type annotation tasks in single-cell genomics. Specifically, we assess the performance of 8 instruction-tuned LLMs across 11 datasets, spanning multiple cell types and species. Our study explores the potential of LLMs to accurately classify and annotate cell types in single-cell RNA sequencing (scRNA-seq) data, while extending their application to multiomics data through cross-modality translation. Additionally, we evaluate the effectiveness of chain-of-thought (CoT) prompting techniques in generating detailed biological insights during the annotation process. The results demonstrate that LLMs can provide robust interpretations of single-cell data without requiring additional fine-tuning, advancing the automation of cell type annotation in genomics research.

Many cellular processes involve information processing and decision making. We can probe these processes at increasing molecular detail. The analysis of heterogeneous data remains a challenge that requires new ways of thinking about cells in quantitative, predictive, and mechanistic ways. We discuss the role of mathematical models in the context of cell-fate decision making systems across the tree of life. Complex multi-cellular organisms have been a particular focus, but single celled organisms also have to sense and respond to their environment. We center our discussion around the idea of design principles which we can learn from observations and modeling, and exploit in order to (re)-design or guide cellular behavior.

In hematology, computational models offer significant potential to improve diagnostic accuracy, streamline workflows, and reduce the tedious work of analyzing single cells in peripheral blood or bone marrow smears. However, clinical adoption of computational models has been hampered by the lack of generalization due to large batch effects, small dataset sizes, and poor performance in transfer learning from natural images. To address these challenges, we introduce DinoBloom, the first foundation model for single cell images in hematology, utilizing a tailored DINOv2 pipeline. Our model is built upon an extensive collection of 13 diverse, publicly available datasets of peripheral blood and bone marrow smears, the most substantial open-source cohort in hematology so far, comprising over 380,000 white blood cell images. To assess its generalization capability, we evaluate it on an external dataset with a challenging domain shift. We show that our model outperforms existing medical and non-medical vision models in (i) linear probing and k-nearest neighbor evaluations for cell-type classification on blood and bone marrow smears and (ii) weakly supervised multiple instance learning for acute myeloid leukemia subtyping by a large margin. A family of four DinoBloom models (small, base, large, and giant) can be adapted for a wide range of downstream applications, be a strong baseline for classification problems, and facilitate the assessment of batch effects in new datasets. All models are available at github.com/marrlab/DinoBloom.

Single-cell transcriptomics enabled the study of cellular heterogeneity in response to perturbations at the resolution of individual cells. However, scaling high-throughput screens (HTSs) to measure cellular responses for many drugs remains a challenge due to technical limitations and, more importantly, the cost of such multiplexed experiments. Thus, transferring information from routinely performed bulk RNA HTS is required to enrich single-cell data meaningfully. We introduce chemCPA, a new encoder-decoder architecture to study the perturbational effects of unseen drugs. We combine the model with an architecture surgery for transfer learning and demonstrate how training on existing bulk RNA HTS datasets can improve generalisation performance. Better generalisation reduces the need for extensive and costly screens at single-cell resolution. We envision that our proposed method will facilitate more efficient experiment designs through its ability to generate in-silico hypotheses, ultimately accelerating drug discovery.

Single-cell RNA sequencing (scRNA-seq) data are often confounded by technical or biological batch effects. Existing deep learning models mitigate these effects but often discard batch-specific information, potentially losing valuable biological insights. We propose a Mixed Effects Deep Learning (MEDL) autoencoder framework that separately models batch-invariant (fixed effects) and batch-specific (random effects) components. By decoupling batch-invariant biological states from batch variations, our framework integrates both into predictive models. Our approach also generates 2D visualizations of how the same cell appears across batches, enhancing interpretability. Retaining both fixed and random effect latent spaces improves classification accuracy. We applied our framework to three datasets spanning the cardiovascular system (Healthy Heart), Autism Spectrum Disorder (ASD), and Acute Myeloid Leukemia (AML). With 147 batches in the Healthy Heart dataset, far exceeding typical numbers, we tested our framework's ability to handle many batches. In the ASD dataset, our approach captured donor heterogeneity between autistic and healthy individuals. In the AML dataset, it distinguished donor heterogeneity despite missing cell types and diseased donors exhibiting both healthy and malignant cells. These results highlight our framework's ability to characterize fixed and random effects, enhance batch effect visualization, and improve prediction accuracy across diverse datasets.

Computational microscopy, in which hardware and algorithms of an imaging system are jointly designed, shows promise for making imaging systems that cost less, perform more robustly, and collect new types of information. Often, the performance of computational imaging systems, especially those that incorporate machine learning, is sample-dependent. Thus, standardized datasets are an essential tool for comparing the performance of different approaches. Here, we introduce the Berkeley Single Cell Computational Microscopy (BSCCM) dataset, which contains over ~12,000,000 images of 400,000 of individual white blood cells. The dataset contains images captured with multiple illumination patterns on an LED array microscope and fluorescent measurements of the abundance of surface proteins that mark different cell types. We hope this dataset will provide a valuable resource for the development and testing of new algorithms in computational microscopy and computer vision with practical biomedical applications.

Generative modeling of single-cell RNA-seq data has shown invaluable potential in community-driven tasks such as trajectory inference, batch effect removal and gene expression generation. However, most recent deep models generating synthetic single cells from noise operate on pre-processed continuous gene expression approximations, ignoring the inherently discrete and over-dispersed nature of single-cell data, which limits downstream applications and hinders the incorporation of robust noise models. Moreover, crucial aspects of deep-learning-based synthetic single-cell generation remain underexplored, such as controllable multi-modal and multi-label generation and its role in the performance enhancement of downstream tasks. This work presents Cell Flow for Generation (CFGen), a flow-based conditional generative model for multi-modal single-cell counts, which explicitly accounts for the discrete nature of the data. Our results suggest improved recovery of crucial biological data characteristics while accounting for novel generative tasks such as conditioning on multiple attributes and boosting rare cell type classification via data augmentation. By showcasing CFGen on a diverse set of biological datasets and settings, we provide evidence of its value to the fields of computational biology and deep generative models.

Recent advances in microscopy have enabled the rapid generation of terabytes of image data in cell biology and biomedical research. Vision-language models (VLMs) offer a promising solution for large-scale biological image analysis, enhancing researchers' efficiency, identifying new image biomarkers, and accelerating hypothesis generation and scientific discovery. However, there is a lack of standardized, diverse, and large-scale vision-language benchmarks to evaluate VLMs' perception and cognition capabilities in biological image understanding. To address this gap, we introduce {\mu}-Bench, an expert-curated benchmark encompassing 22 biomedical tasks across various scientific disciplines (biology, pathology), microscopy modalities (electron, fluorescence, light), scales (subcellular, cellular, tissue), and organisms in both normal and abnormal states. We evaluate state-of-the-art biomedical, pathology, and general VLMs on {\mu}-Bench and find that: i) current models struggle on all categories, even for basic tasks such as distinguishing microscopy modalities; ii) current specialist models fine-tuned on biomedical data often perform worse than generalist models; iii) fine-tuning in specific microscopy domains can cause catastrophic forgetting, eroding prior biomedical knowledge encoded in their base model. iv) weight interpolation between fine-tuned and pre-trained models offers one solution to forgetting and improves general performance across biomedical tasks. We release {\mu}-Bench under a permissive license to accelerate the research and development of microscopy foundation models.

Cell segmentation is a critical step for quantitative single-cell analysis in microscopy images. Existing cell segmentation methods are often tailored to specific modalities or require manual interventions to specify hyperparameters in different experimental settings. Here, we present a multi-modality cell segmentation benchmark, comprising over 1500 labeled images derived from more than 50 diverse biological experiments. The top participants developed a Transformer-based deep-learning algorithm that not only exceeds existing methods, but can also be applied to diverse microscopy images across imaging platforms and tissue types without manual parameter adjustments. This benchmark and the improved algorithm offer promising avenues for more accurate and versatile cell analysis in microscopy imaging.

Nasal Cytology is a new and efficient clinical technique to diagnose rhinitis and allergies that is not much widespread due to the time-consuming nature of cell counting; that is why AI-aided counting could be a turning point for the diffusion of this technique. In this article we present the first dataset of rhino-cytological field images: the NCD (Nasal Cytology Dataset), aimed to train and deploy Object Detection models to support physicians and biologists during clinical practice. The real distribution of the cytotypes, populating the nasal mucosa has been replicated, sampling images from slides of clinical patients, and manually annotating each cell found on them. The correspondent object detection task presents non'trivial issues associated with the strong class imbalancement, involving the rarest cell types. This work contributes to some of open challenges by presenting a novel machine learning-based approach to aid the automated detection and classification of nasal mucosa cells: the DETR and YOLO models shown good performance in detecting cells and classifying them correctly, revealing great potential to accelerate the work of rhinology experts.

Fluorescence labeling is the standard approach to reveal cellular structures and other subcellular constituents for microscopy images. However, this invasive procedure may perturb or even kill the cells and the procedure itself is highly time-consuming and complex. Recently, in silico labeling has emerged as a promising alternative, aiming to use machine learning models to directly predict the fluorescently labeled images from label-free microscopy. In this paper, we propose a deep learning-based in silico labeling method for the Light My Cells challenge. Built upon pix2pix, our proposed method can be trained using the partially labeled datasets with an adaptive loss. Moreover, we explore the effectiveness of several training strategies to handle different input modalities, such as training them together or separately. The results show that our method achieves promising performance for in silico labeling. Our code is available at https://github.com/MedICL-VU/LightMyCells.

Instance segmentation of neurons in volumetric light microscopy images of nervous systems enables groundbreaking research in neuroscience by facilitating joint functional and morphological analyses of neural circuits at cellular resolution. Yet said multi-neuron light microscopy data exhibits extremely challenging properties for the task of instance segmentation: Individual neurons have long-ranging, thin filamentous and widely branching morphologies, multiple neurons are tightly inter-weaved, and partial volume effects, uneven illumination and noise inherent to light microscopy severely impede local disentangling as well as long-range tracing of individual neurons. These properties reflect a current key challenge in machine learning research, namely to effectively capture long-range dependencies in the data. While respective methodological research is buzzing, to date methods are typically benchmarked on synthetic datasets. To address this gap, we release the FlyLight Instance Segmentation Benchmark (FISBe) dataset, the first publicly available multi-neuron light microscopy dataset with pixel-wise annotations. In addition, we define a set of instance segmentation metrics for benchmarking that we designed to be meaningful with regard to downstream analyses. Lastly, we provide three baselines to kick off a competition that we envision to both advance the field of machine learning regarding methodology for capturing long-range data dependencies, and facilitate scientific discovery in basic neuroscience.

Confocal fluorescence microscopy is one of the most accessible and widely used imaging techniques for the study of biological processes. Scanning confocal microscopy allows the capture of high-quality images from 3D samples, yet suffers from well-known limitations such as photobleaching and phototoxicity of specimens caused by intense light exposure, which limits its use in some applications, especially for living cells. Cellular damage can be alleviated by changing imaging parameters to reduce light exposure, often at the expense of image quality. Machine/deep learning methods for single-image super-resolution (SISR) can be applied to restore image quality by upscaling lower-resolution (LR) images to produce high-resolution images (HR). These SISR methods have been successfully applied to photo-realistic images due partly to the abundance of publicly available data. In contrast, the lack of publicly available data partly limits their application and success in scanning confocal microscopy. In this paper, we introduce a large scanning confocal microscopy dataset named SR-CACO-2 that is comprised of low- and high-resolution image pairs marked for three different fluorescent markers. It allows the evaluation of performance of SISR methods on three different upscaling levels (X2, X4, X8). SR-CACO-2 contains the human epithelial cell line Caco-2 (ATCC HTB-37), and it is composed of 22 tiles that have been translated in the form of 9,937 image patches for experiments with SISR methods. Given the new SR-CACO-2 dataset, we also provide benchmarking results for 15 state-of-the-art methods that are representative of the main SISR families. Results show that these methods have limited success in producing high-resolution textures, indicating that SR-CACO-2 represents a challenging problem. Our dataset, code and pretrained weights are available: https://github.com/sbelharbi/sr-caco-2.

Multiplex immunofluorescence and immunohistochemistry benefit patients by allowing cancer pathologists to identify several proteins expressed on the surface of cells, enabling cell classification, better understanding of the tumour micro-environment, more accurate diagnoses, prognoses, and tailored immunotherapy based on the immune status of individual patients. However, they are expensive and time consuming processes which require complex staining and imaging techniques by expert technicians. Hoechst staining is much cheaper and easier to perform, but is not typically used in this case as it binds to DNA rather than to the proteins targeted by immunofluorescent techniques, and it was not previously thought possible to differentiate cells expressing these proteins based only on DNA morphology. In this work we show otherwise, training a deep convolutional neural network to identify cells expressing three proteins (T lymphocyte markers CD3 and CD8, and the B lymphocyte marker CD20) with greater than 90% precision and recall, from Hoechst 33342 stained tissue only. Our model learns previously unknown morphological features associated with expression of these proteins which can be used to accurately differentiate lymphocyte subtypes for use in key prognostic metrics such as assessment of immune cell infiltration,and thereby predict and improve patient outcomes without the need for costly multiplex immunofluorescence.

Unlike color photography images, which are consistently encoded into RGB channels, biological images encompass various modalities, where the type of microscopy and the meaning of each channel varies with each experiment. Importantly, the number of channels can range from one to a dozen and their correlation is often comparatively much lower than RGB, as each of them brings specific information content. This aspect is largely overlooked by methods designed out of the bioimage field, and current solutions mostly focus on intra-channel spatial attention, often ignoring the relationship between channels, yet crucial in most biological applications. Importantly, the variable channel type and count prevent the projection of several experiments to a unified representation for large scale pre-training. In this study, we propose ChAda-ViT, a novel Channel Adaptive Vision Transformer architecture employing an Inter-Channel Attention mechanism on images with an arbitrary number, order and type of channels. We also introduce IDRCell100k, a bioimage dataset with a rich set of 79 experiments covering 7 microscope modalities, with a multitude of channel types, and channel counts varying from 1 to 10 per experiment. Our proposed architecture, trained in a self-supervised manner, outperforms existing approaches in several biologically relevant downstream tasks. Additionally, it can be used to bridge the gap for the first time between assays with different microscopes, channel numbers or types by embedding various image and experimental modalities into a unified biological image representation. The latter should facilitate interdisciplinary studies and pave the way for better adoption of deep learning in biological image-based analyses. Code and Data to be released soon.

In this paper, we propose a hybrid approach for multi-object microbial cell segmentation. The approach combines an ML-based detection with a geometry-aware variational-based segmentation using B-splines that are parametrized based on a geometric model of the cell shape. The detection is done first using YOLOv5. In a second step, each detected cell is segmented individually. Thus, the segmentation only needs to be done on a per-cell basis, which makes it amenable to a variational approach that incorporates prior knowledge on the geometry. Here, the contour of the segmentation is modelled as closed uniform cubic B-spline, whose control points are parametrized using the known cell geometry. Compared to purely ML-based segmentation approaches, which need accurate segmentation maps as training data that are very laborious to produce, our method just needs bounding boxes as training data. Still, the proposed method performs on par with ML-based segmentation approaches usually used in this context. We study the performance of the proposed method on time-lapse microscopy data of Corynebacterium glutamicum.

In biological research, fluorescence staining is a key technique to reveal the locations and morphology of subcellular structures. However, it is slow, expensive, and harmful to cells. In this paper, we model it as a deep learning task termed subcellular structure prediction (SSP), aiming to predict the 3D fluorescent images of multiple subcellular structures from a 3D transmitted-light image. Unfortunately, due to the limitations of current biotechnology, each image is partially labeled in SSP. Besides, naturally, subcellular structures vary considerably in size, which causes the multi-scale issue of SSP. To overcome these challenges, we propose Re-parameterizing Mixture-of-Diverse-Experts (RepMode), a network that dynamically organizes its parameters with task-aware priors to handle specified single-label prediction tasks. In RepMode, the Mixture-of-Diverse-Experts (MoDE) block is designed to learn the generalized parameters for all tasks, and gating re-parameterization (GatRep) is performed to generate the specialized parameters for each task, by which RepMode can maintain a compact practical topology exactly like a plain network, and meanwhile achieves a powerful theoretical topology. Comprehensive experiments show that RepMode can achieve state-of-the-art overall performance in SSP.

Understanding the origin(s) of life (OoL) is a fundamental challenge for science in the 21st century. Research on OoL spans many disciplines, including chemistry, physics, biology, planetary sciences, computer science, mathematics and philosophy. The sheer number of different scientific perspectives relevant to the problem has resulted in the coexistence of diverse tools, techniques, data, and software in OoL studies. This has made communication between the disciplines relevant to the OoL extremely difficult because the interpretation of data, analyses, or standards of evidence can vary dramatically. Here, we hope to bridge this wide field of study by providing common ground via the consolidation of tools and techniques rather than positing a unifying view on how life emerges. We review the common tools and techniques that have been used significantly in OoL studies in recent years. In particular, we aim to identify which information is most relevant for comparing and integrating the results of experimental analyses into mathematical and computational models. This review aims to provide a baseline expectation and understanding of technical aspects of origins research, rather than being a primer on any particular topic. As such, it spans broadly -- from analytical chemistry to mathematical models -- and highlights areas of future work that will benefit from a multidisciplinary approach to tackling the mystery of life's origin. Ultimately, we hope to empower a new generation of OoL scientists by reviewing how they can investigate life's origin, rather than dictating how to think about the problem.

In the development of science, accurate and reproducible documentation of the experimental process is crucial. Automatic recognition of the actions in experiments from videos would help experimenters by complementing the recording of experiments. Towards this goal, we propose FineBio, a new fine-grained video dataset of people performing biological experiments. The dataset consists of multi-view videos of 32 participants performing mock biological experiments with a total duration of 14.5 hours. One experiment forms a hierarchical structure, where a protocol consists of several steps, each further decomposed into a set of atomic operations. The uniqueness of biological experiments is that while they require strict adherence to steps described in each protocol, there is freedom in the order of atomic operations. We provide hierarchical annotation on protocols, steps, atomic operations, object locations, and their manipulation states, providing new challenges for structured activity understanding and hand-object interaction recognition. To find out challenges on activity understanding in biological experiments, we introduce baseline models and results on four different tasks, including (i) step segmentation, (ii) atomic operation detection (iii) object detection, and (iv) manipulated/affected object detection. Dataset and code are available from https://github.com/aistairc/FineBio.

The segmentation of cell nuclei in tissue images stained with the blood dye hematoxylin and eosin (H&E) is essential for various clinical applications and analyses. Due to the complex characteristics of cellular morphology, a large receptive field is considered crucial for generating high-quality segmentation. However, previous methods face challenges in achieving a balance between the receptive field and computational burden. To address this issue, we propose LKCell, a high-accuracy and efficient cell segmentation method. Its core insight lies in unleashing the potential of large convolution kernels to achieve computationally efficient large receptive fields. Specifically, (1) We transfer pre-trained large convolution kernel models to the medical domain for the first time, demonstrating their effectiveness in cell segmentation. (2) We analyze the redundancy of previous methods and design a new segmentation decoder based on large convolution kernels. It achieves higher performance while significantly reducing the number of parameters. We evaluate our method on the most challenging benchmark and achieve state-of-the-art results (0.5080 mPQ) in cell nuclei instance segmentation with only 21.6% FLOPs compared with the previous leading method. Our source code and models are available at https://github.com/hustvl/LKCell.

Featurizing microscopy images for use in biological research remains a significant challenge, especially for large-scale experiments spanning millions of images. This work explores the scaling properties of weakly supervised classifiers and self-supervised masked autoencoders (MAEs) when training with increasingly larger model backbones and microscopy datasets. Our results show that ViT-based MAEs outperform weakly supervised classifiers on a variety of tasks, achieving as much as a 11.5% relative improvement when recalling known biological relationships curated from public databases. Additionally, we develop a new channel-agnostic MAE architecture (CA-MAE) that allows for inputting images of different numbers and orders of channels at inference time. We demonstrate that CA-MAEs effectively generalize by inferring and evaluating on a microscopy image dataset (JUMP-CP) generated under different experimental conditions with a different channel structure than our pretraining data (RPI-93M). Our findings motivate continued research into scaling self-supervised learning on microscopy data in order to create powerful foundation models of cellular biology that have the potential to catalyze advancements in drug discovery and beyond.

Nuclear segmentation, classification and quantification within Haematoxylin & Eosin stained histology images enables the extraction of interpretable cell-based features that can be used in downstream explainable models in computational pathology (CPath). However, automatic recognition of different nuclei is faced with a major challenge in that there are several different types of nuclei, some of them exhibiting large intraclass variability. In this work, we propose an approach that combine Separable-HoverNet and Instance-YOLOv5 to indentify colon nuclei small and unbalanced. Our approach can achieve mPQ+ 0.389 on the Segmentation and Classification-Preliminary Test Dataset and r2 0.599 on the Cellular Composition-Preliminary Test Dataset on ISBI 2022 CoNIC Challenge.

Efficient Human Epithelial-2 (HEp-2) cell image classification can facilitate the diagnosis of many autoimmune diseases. This paper presents an automatic framework for this classification task, by utilizing the deep convolutional neural networks (CNNs) which have recently attracted intensive attention in visual recognition. This paper elaborates the important components of this framework, discusses multiple key factors that impact the efficiency of training a deep CNN, and systematically compares this framework with the well-established image classification models in the literature. Experiments on benchmark datasets show that i) the proposed framework can effectively outperform existing models by properly applying data augmentation; ii) our CNN-based framework demonstrates excellent adaptability across different datasets, which is highly desirable for classification under varying laboratory settings. Our system is ranked high in the cell image classification competition hosted by ICPR 2014.

Inferring biological relationships from cellular phenotypes in high-content microscopy screens provides significant opportunity and challenge in biological research. Prior results have shown that deep vision models can capture biological signal better than hand-crafted features. This work explores how self-supervised deep learning approaches scale when training larger models on larger microscopy datasets. Our results show that both CNN- and ViT-based masked autoencoders significantly outperform weakly supervised baselines. At the high-end of our scale, a ViT-L/8 trained on over 3.5-billion unique crops sampled from 93-million microscopy images achieves relative improvements as high as 28% over our best weakly supervised baseline at inferring known biological relationships curated from public databases. Relevant code and select models released with this work can be found at: https://github.com/recursionpharma/maes_microscopy.

The galaxy population is strongly bimodal in both colour and morphology, and the two measures correlate strongly, with most blue galaxies being late-types (spirals) and most early-types, typically ellipticals, being red. This observation has led to the use of colour as a convenient selection criteria to make samples which are then labelled by morphology. Such use of colour as a proxy for morphology results in necessarily impure and incomplete samples. In this paper, we make use of the morphological labels produced by Galaxy Zoo to measure how incomplete and impure such samples are, considering optical (ugriz), NUV and NIR (JHK) bands. The best single colour optical selection is found using a threshold of g-r = 0.742, but this still results in a sample where only 56% of red galaxies are smooth and 56% of smooth galaxies are red. Use of the NUV gives some improvement over purely optical bands, particularly for late-types, but still results in low purity/completeness for early-types. No significant improvement is found by adding NIR bands. With any two bands, including NUV, a sample of early-types with greater than two-thirds purity cannot be constructed. Advances in quantitative galaxy morphologies have made colour-morphology proxy selections largely unnecessary going forward; where such assumptions are still required, we recommend studies carefully consider the implications of sample incompleteness/impurity.

Intracellular lasers are emerging as powerful biosensors for multiplexed tracking and precision sensing of cells and their microenvironment. This sensing capacity is enabled by quantifying their narrow-linewidth emission spectra, which is presently challenging to do at high speeds. In this work, we demonstrate rapid snapshot hyperspectral imaging of intracellular lasers. Using integral field mapping with a microlens array and a diffraction grating, we obtain images of the spatial and spectral intensity distribution from a single camera acquisition. We demonstrate widefield hyperspectral imaging over a 3times3 mm^2 field of view and volumetric imaging over 250times250times800 mum^3 volumes with a spatial resolution of 5 mum and a spectral resolution of less than 0.8 nm. We evaluate the performance and outline the challenges and strengths of snapshot methods in the context of characterising the emission from intracellular lasers. This method offers new opportunities for a diverse range of applications, including high-throughput and long-term biosensing with intracellular lasers.

Cell instance segmentation in fluorescence microscopy images is becoming essential for cancer dynamics and prognosis. Data extracted from cancer dynamics allows to understand and accurately model different metabolic processes such as proliferation. This enables customized and more precise cancer treatments. However, accurate cell instance segmentation, necessary for further cell tracking and behavior analysis, is still challenging in scenarios with high cell concentration and overlapping edges. Within this framework, we propose a novel cell instance segmentation approach based on the well-known U-Net architecture. To enforce the learning of morphological information per pixel, a deep distance transformer (DDT) acts as a back-bone model. The DDT output is subsequently used to train a top-model. The following top-models are considered: a three-class (e.g., foreground, background and cell border) U-net, and a watershed transform. The obtained results suggest a performance boost over traditional U-Net architectures. This opens an interesting research line around the idea of injecting morphological information into a fully convolutional model.

Practitioners frequently aim to infer an unobserved population trajectory using sample snapshots at multiple time points. For instance, in single-cell sequencing, scientists would like to learn how gene expression evolves over time. But sequencing any cell destroys that cell. So we cannot access any cell's full trajectory, but we can access snapshot samples from many cells. Stochastic differential equations are commonly used to analyze systems with full individual-trajectory access; since here we have only sample snapshots, these methods are inapplicable. The deep learning community has recently explored using Schr\"odinger bridges (SBs) and their extensions to estimate these dynamics. However, these methods either (1) interpolate between just two time points or (2) require a single fixed reference dynamic within the SB, which is often just set to be Brownian motion. But learning piecewise from adjacent time points can fail to capture long-term dependencies. And practitioners are typically able to specify a model class for the reference dynamic but not the exact values of the parameters within it. So we propose a new method that (1) learns the unobserved trajectories from sample snapshots across multiple time points and (2) requires specification only of a class of reference dynamics, not a single fixed one. In particular, we suggest an iterative projection method inspired by Schr\"odinger bridges; we alternate between learning a piecewise SB on the unobserved trajectories and using the learned SB to refine our best guess for the dynamics within the reference class. We demonstrate the advantages of our method via a well-known simulated parametric model from ecology, simulated and real data from systems biology, and real motion-capture data.

Holistic 3D modeling of molecularly defined brain structures is crucial for understanding complex brain functions. Emerging tissue profiling technologies enable the construction of a comprehensive atlas of the mammalian brain with sub-cellular resolution and spatially resolved gene expression data. However, such tera-scale volumetric datasets present significant computational challenges in understanding complex brain functions within their native 3D spatial context. Here, we propose the novel generative approach Tera-MIND, which can simulate Tera-scale Mouse braINs in 3D using a patch-based and boundary-aware Diffusion model. Taking spatial transcriptomic data as the conditional input, we generate virtual mouse brains with comprehensive cellular morphological detail at teravoxel scale. Through the lens of 3D gene-gene self-attention, we identify spatial molecular interactions for key transcriptomic pathways in the murine brain, exemplified by glutamatergic and dopaminergic neuronal systems. Importantly, these in-silico biological findings are consistent and reproducible across three tera-scale virtual mouse brains. Therefore, Tera-MIND showcases a promising path toward efficient and generative simulations of whole organ systems for biomedical research. Project website: http://musikisomorphie.github.io/Tera-MIND.html{https}

Understanding how deep learning models predict oncology patient risk can provide critical insights into disease progression, support clinical decision-making, and pave the way for trustworthy and data-driven precision medicine. Building on recent advances in the spatial modeling of the tumor microenvironment using graph neural networks, we present an explainable cell graph (xCG) approach for survival prediction. We validate our model on a public cohort of imaging mass cytometry (IMC) data for 416 cases of lung adenocarcinoma. We explain survival predictions in terms of known phenotypes on the cell level by computing risk attributions over cell graphs, for which we propose an efficient grid-based layer-wise relevance propagation (LRP) method. Our ablation studies highlight the importance of incorporating the cancer stage and model ensembling to improve the quality of risk estimates. Our xCG method, together with the IMC data, is made publicly available to support further research.

Multi-cellular robot design aims to create robots comprised of numerous cells that can be efficiently controlled to perform diverse tasks. Previous research has demonstrated the ability to generate robots for various tasks, but these approaches often optimize robots directly in the vast design space, resulting in robots with complicated morphologies that are hard to control. In response, this paper presents a novel coarse-to-fine method for designing multi-cellular robots. Initially, this strategy seeks optimal coarse-grained robots and progressively refines them. To mitigate the challenge of determining the precise refinement juncture during the coarse-to-fine transition, we introduce the Hyperbolic Embeddings for Robot Design (HERD) framework. HERD unifies robots of various granularity within a shared hyperbolic space and leverages a refined Cross-Entropy Method for optimization. This framework enables our method to autonomously identify areas of exploration in hyperbolic space and concentrate on regions demonstrating promise. Finally, the extensive empirical studies on various challenging tasks sourced from EvoGym show our approach's superior efficiency and generalization capability.

Computing in the life sciences has undergone a transformative evolution, from early computational models in the 1950s to the applications of artificial intelligence (AI) and machine learning (ML) seen today. This paper highlights key milestones and technological advancements through the historical development of computing in the life sciences. The discussion includes the inception of computational models for biological processes, the advent of bioinformatics tools, and the integration of AI/ML in modern life sciences research. Attention is given to AI-enabled tools used in the life sciences, such as scientific large language models and bio-AI tools, examining their capabilities, limitations, and impact to biological risk. This paper seeks to clarify and establish essential terminology and concepts to ensure informed decision-making and effective communication across disciplines.

Traditional fluorescence staining is phototoxic to live cells, slow, and expensive; thus, the subcellular structure prediction (SSP) from transmitted light (TL) images is emerging as a label-free, faster, low-cost alternative. However, existing approaches utilize 3D networks for one-to-one voxel level dense prediction, which necessitates a frequent and time-consuming Z-axis imaging process. Moreover, 3D convolutions inevitably lead to significant computation and GPU memory overhead. Therefore, we propose an efficient framework, SparseSSP, predicting fluorescent intensities within the target voxel grid in an efficient paradigm instead of relying entirely on 3D topologies. In particular, SparseSSP makes two pivotal improvements to prior works. First, SparseSSP introduces a one-to-many voxel mapping paradigm, which permits the sparse TL slices to reconstruct the subcellular structure. Secondly, we propose a hybrid dimensions topology, which folds the Z-axis information into channel features, enabling the 2D network layers to tackle SSP under low computational cost. We conduct extensive experiments to validate the effectiveness and advantages of SparseSSP on diverse sparse imaging ratios, and our approach achieves a leading performance compared to pure 3D topologies. SparseSSP reduces imaging frequencies compared to previous dense-view SSP (i.e., the number of imaging is reduced up to 87.5% at most), which is significant in visualizing rapid biological dynamics on low-cost devices and samples.

Structured illumination microscopy (SIM) has become an important technique for optical super-resolution imaging because it allows a doubling of image resolution at speeds compatible for live-cell imaging. However, the reconstruction of SIM images is often slow and prone to artefacts. Here we propose a versatile reconstruction method, ML-SIM, which makes use of machine learning. The model is an end-to-end deep residual neural network that is trained on a simulated data set to be free of common SIM artefacts. ML-SIM is thus robust to noise and irregularities in the illumination patterns of the raw SIM input frames. The reconstruction method is widely applicable and does not require the acquisition of experimental training data. Since the training data are generated from simulations of the SIM process on images from generic libraries the method can be efficiently adapted to specific experimental SIM implementations. The reconstruction quality enabled by our method is compared with traditional SIM reconstruction methods, and we demonstrate advantages in terms of noise, reconstruction fidelity and contrast for both simulated and experimental inputs. In addition, reconstruction of one SIM frame typically only takes ~100ms to perform on PCs with modern Nvidia graphics cards, making the technique compatible with real-time imaging. The full implementation and the trained networks are available at http://ML-SIM.com.

Object segmentation is an important step in the workflow of computational pathology. Deep learning based models generally require large amount of labeled data for precise and reliable prediction. However, collecting labeled data is expensive because it often requires expert knowledge, particularly in medical imaging domain where labels are the result of a time-consuming analysis made by one or more human experts. As nuclei, cells and glands are fundamental objects for downstream analysis in computational pathology/cytology, in this paper we propose a simple CNN-based approach to speed up collecting annotations for these objects which requires minimum interaction from the annotator. We show that for nuclei and cells in histology and cytology images, one click inside each object is enough for NuClick to yield a precise annotation. For multicellular structures such as glands, we propose a novel approach to provide the NuClick with a squiggle as a guiding signal, enabling it to segment the glandular boundaries. These supervisory signals are fed to the network as auxiliary inputs along with RGB channels. With detailed experiments, we show that NuClick is adaptable to the object scale, robust against variations in the user input, adaptable to new domains, and delivers reliable annotations. An instance segmentation model trained on masks generated by NuClick achieved the first rank in LYON19 challenge. As exemplar outputs of our framework, we are releasing two datasets: 1) a dataset of lymphocyte annotations within IHC images, and 2) a dataset of segmented WBCs in blood smear images.

The simulation of the metabolism in mammalian cells becomes a severe problem if spatial distributions must be taken into account. Especially the cytoplasm has a very complex geometric structure which cannot be handled by standard discretization techniques. In the present paper we propose a homogenization technique for computing effective diffusion constants. This is accomplished by using a two-step strategy. The first step consists of an analytic homogenization from the smallest to an intermediate scale. The homogenization error is estimated by comparing the analytic diffusion constant with a numerical estimate obtained by using real cell geometries. The second step consists of a random homogenization. Since no analytical solution is known to this homogenization problem, a numerical approximation algorithm is proposed. Although rather expensive this algorithm provides a reasonable estimate of the homogenized diffusion constant.

The Ultra-Violet Optical Telescope on the Swift spacecraft has observed hundreds of supernovae, covering all major types and most subtypes. Here we introduce the Swift Optical/Ultraviolet Supernova Archive (SOUSA), which will contain all of the supernova images and photometry. We describe the observation and reduction procedures and how they impact the final data. We show photometry from well-observed examples of most supernova classes, whose absolute magnitudes and colors may be used to infer supernova types in the absence of a spectrum. A full understanding of the variety within classes and a robust photometric separation of the groups requires a larger sample, which will be provided by the final archive. The data from the existing Swift supernovae are also useful for planning future observations with Swift as well as future UV observatories.

As a powerful tool for characterizing cellular subpopulations and cellular heterogeneity, single cell RNA sequencing (scRNA-seq) technology offers advantages of high throughput and multidimensional analysis. However, the process of data acquisition is often constrained by high cost and limited sample availability. To overcome these limitations, we propose a hybrid model based on Diffusion model and White-Box transformer that aims to generate synthetic and biologically plausible scRNA-seq data. Diffusion model progressively introduce noise into the data and then recover the original data through a denoising process, a forward and reverse process that is particularly suitable for generating complex data distributions. White-Box transformer is a deep learning architecture that emphasizes mathematical interpretability. By minimizing the encoding rate of the data and maximizing the sparsity of the representation, it not only reduces the computational burden, but also provides clear insight into underlying structure. Our White-Box Diffusion Transformer combines the generative capabilities of Diffusion model with the mathematical interpretability of White-Box transformer. Through experiments using six different single-cell RNA-Seq datasets, we visualize both generated and real data using t-SNE dimensionality reduction technique, as well as quantify similarity between generated and real data using various metrics to demonstrate comparable performance of White-Box Diffusion Transformer and Diffusion Transformer in generating scRNA-seq data alongside significant improvements in training efficiency and resource utilization. Our code is available at https://github.com/lingximamo/White-Box-Diffusion-Transformer

Single cell analysis of human skeletal muscle (SM) tissue cross-sections is a fundamental tool for understanding many neuromuscular disorders. For this analysis to be reliable and reproducible, identification of individual fibres within microscopy images (segmentation) of SM tissue should be automatic and precise. Biomedical scientists in this field currently rely on custom tools and general machine learning (ML) models, both followed by labour intensive and subjective manual interventions to fine-tune segmentation. We believe that fully automated, precise, reproducible segmentation is possible by training ML models. However, in this important biomedical domain, there are currently no good quality, publicly available annotated imaging datasets available for ML model training. In this paper we release NCL-SM: a high quality bioimaging dataset of 46 human SM tissue cross-sections from both healthy control subjects and from patients with genetically diagnosed muscle pathology. These images include > 50k manually segmented muscle fibres (myofibres). In addition we also curated high quality myofibre segmentations, annotating reasons for rejecting low quality myofibres and low quality regions in SM tissue images, making these annotations completely ready for downstream analysis. This, we believe, will pave the way for development of a fully automatic pipeline that identifies individual myofibres within images of tissue sections and, in particular, also classifies individual myofibres that are fit for further analysis.

With the rapid development of computational pathology, many AI-assisted diagnostic tasks have emerged. Cellular nuclei segmentation can segment various types of cells for downstream analysis, but it relies on predefined categories and lacks flexibility. Moreover, pathology visual question answering can perform image-level understanding but lacks region-level detection capability. To address this, we propose a new benchmark called Pathology Visual Grounding (PathVG), which aims to detect regions based on expressions with different attributes. To evaluate PathVG, we create a new dataset named RefPath which contains 27,610 images with 33,500 language-grounded boxes. Compared to visual grounding in other domains, PathVG presents pathological images at multi-scale and contains expressions with pathological knowledge. In the experimental study, we found that the biggest challenge was the implicit information underlying the pathological expressions. Based on this, we proposed Pathology Knowledge-enhanced Network (PKNet) as the baseline model for PathVG. PKNet leverages the knowledge-enhancement capabilities of Large Language Models (LLMs) to convert pathological terms with implicit information into explicit visual features, and fuses knowledge features with expression features through the designed Knowledge Fusion Module (KFM). The proposed method achieves state-of-the-art performance on the PathVG benchmark.

Wood species identification plays a crucial role in various industries, from ensuring the legality of timber products to advancing ecological conservation efforts. This paper introduces WoodYOLO, a novel object detection algorithm specifically designed for microscopic wood fiber analysis. Our approach adapts the YOLO architecture to address the challenges posed by large, high-resolution microscopy images and the need for high recall in localization of the cell type of interest (vessel elements). Our results show that WoodYOLO significantly outperforms state-of-the-art models, achieving performance gains of 12.9% and 6.5% in F2 score over YOLOv10 and YOLOv7, respectively. This improvement in automated wood cell type localization capabilities contributes to enhancing regulatory compliance, supporting sustainable forestry practices, and promoting biodiversity conservation efforts globally.

Numerous biological and physical processes can be modeled as systems of interacting entities evolving continuously over time, e.g. the dynamics of communicating cells or physical particles. Learning the dynamics of such systems is essential for predicting the temporal evolution of populations across novel samples and unseen environments. Flow-based models allow for learning these dynamics at the population level - they model the evolution of the entire distribution of samples. However, current flow-based models are limited to a single initial population and a set of predefined conditions which describe different dynamics. We argue that multiple processes in natural sciences have to be represented as vector fields on the Wasserstein manifold of probability densities. That is, the change of the population at any moment in time depends on the population itself due to the interactions between samples. In particular, this is crucial for personalized medicine where the development of diseases and their respective treatment response depends on the microenvironment of cells specific to each patient. We propose Meta Flow Matching (MFM), a practical approach to integrating along these vector fields on the Wasserstein manifold by amortizing the flow model over the initial populations. Namely, we embed the population of samples using a Graph Neural Network (GNN) and use these embeddings to train a Flow Matching model. This gives MFM the ability to generalize over the initial distributions unlike previously proposed methods. We demonstrate the ability of MFM to improve prediction of individual treatment responses on a large scale multi-patient single-cell drug screen dataset.

In an era of increasing pressure to achieve sustainable agriculture, the optimization of livestock feed for enhancing yield and minimizing environmental impact is a paramount objective. This study presents a pioneering approach towards this goal, using rumen microbiome data to predict the efficacy of feed additives in dairy cattle. We collected an extensive dataset that includes methane emissions from 2,190 Holstein cows distributed across 34 distinct sites. The cows were divided into control and experimental groups in a double-blind, unbiased manner, accounting for variables such as age, days in lactation, and average milk yield. The experimental groups were administered one of four leading commercial feed additives: Agolin, Kexxtone, Allimax, and Relyon. Methane emissions were measured individually both before the administration of additives and over a subsequent 12-week period. To develop our predictive model for additive efficacy, rumen microbiome samples were collected from 510 cows from the same herds prior to the study's onset. These samples underwent deep metagenomic shotgun sequencing, yielding an average of 15.7 million reads per sample. Utilizing innovative artificial intelligence techniques we successfully estimated the efficacy of these feed additives across different farms. The model's robustness was further confirmed through validation with independent cohorts, affirming its generalizability and reliability. Our results underscore the transformative capability of using targeted feed additive strategies to both optimize dairy yield and milk composition, and to significantly reduce methane emissions. Specifically, our predictive model demonstrates a scenario where its application could guide the assignment of additives to farms where they are most effective. In doing so, we could achieve an average potential reduction of over 27\% in overall emissions.

A Recurrent Neural Network (RNN) was used to perform video frame prediction of microbial growth for a population of two mutants of Pseudomonas aeruginosa. The RNN was trained on videos of 20 frames that were acquired using fluorescence microscopy and microfluidics. The network predicted the last 10 frames of each video, and the accuracy's of the predictions was assessed by comparing raw images, population curves, and the number and size of individual colonies. Overall, we found the predictions to be accurate using this approach. The implications this result has on designing autonomous experiments in microbiology, and the steps that can be taken to make the predictions even more accurate, are discussed.

Star-convex shapes arise across bio-microscopy and radiology in the form of nuclei, nodules, metastases, and other units. Existing instance segmentation networks for such structures train on densely labeled instances for each dataset, which requires substantial and often impractical manual annotation effort. Further, significant reengineering or finetuning is needed when presented with new datasets and imaging modalities due to changes in contrast, shape, orientation, resolution, and density. We present AnyStar, a domain-randomized generative model that simulates synthetic training data of blob-like objects with randomized appearance, environments, and imaging physics to train general-purpose star-convex instance segmentation networks. As a result, networks trained using our generative model do not require annotated images from unseen datasets. A single network trained on our synthesized data accurately 3D segments C. elegans and P. dumerilii nuclei in fluorescence microscopy, mouse cortical nuclei in micro-CT, zebrafish brain nuclei in EM, and placental cotyledons in human fetal MRI, all without any retraining, finetuning, transfer learning, or domain adaptation. Code is available at https://github.com/neel-dey/AnyStar.

Task-specific deep learning models in histopathology offer promising opportunities for improving diagnosis, clinical research, and precision medicine. However, development of such models is often limited by availability of high-quality data. Foundation models in histopathology that learn general representations across a wide range of tissue types, diagnoses, and magnifications offer the potential to reduce the data, compute, and technical expertise necessary to develop task-specific deep learning models with the required level of model performance. In this work, we describe the development and evaluation of foundation models for histopathology via self-supervised learning (SSL). We first establish a diverse set of benchmark tasks involving 17 unique tissue types and 12 unique cancer types and spanning different optimal magnifications and task types. Next, we use this benchmark to explore and evaluate histopathology-specific SSL methods followed by further evaluation on held out patch-level and weakly supervised tasks. We found that standard SSL methods thoughtfully applied to histopathology images are performant across our benchmark tasks and that domain-specific methodological improvements can further increase performance. Our findings reinforce the value of using domain-specific SSL methods in pathology, and establish a set of high quality foundation models to enable further research across diverse applications.

Domain generalization is critical for real-world applications of machine learning to microscopy images, including histopathology and fluorescence imaging. Artifacts in these modalities arise through a complex combination of factors relating to tissue collection and laboratory processing, as well as factors intrinsic to patient samples. In fluorescence imaging, these artifacts stem from variations across experimental batches. The complexity and subtlety of these artifacts make the enumeration of data domains intractable. Therefore, augmentation-based methods of domain generalization that require domain identifiers and manual fine-tuning are inadequate in this setting. To overcome this challenge, we introduce ContriMix, a domain generalization technique that learns to generate synthetic images by disentangling and permuting the biological content ("content") and technical variations ("attributes") in microscopy images. ContriMix does not rely on domain identifiers or handcrafted augmentations and makes no assumptions about the input characteristics of images. We assess the performance of ContriMix on two pathology datasets dealing with patch classification and Whole Slide Image label prediction tasks respectively (Camelyon17-WILDS and RCC subtyping), and one fluorescence microscopy dataset (RxRx1-WILDS). Without any access to domain identifiers at train or test time, ContriMix performs similar or better than current state-of-the-art methods in all these datasets, motivating its usage for microscopy image analysis in real-world settings where domain information is hard to come by. The code for ContriMix can be found at https://gitlab.com/huutan86/contrimix

Many examples of cooperation exist in biology. In chemical systems however, which can sometimes be quite complex, we do not appear to observe intricate cooperative interactions. A key question for the origin of life, is then how can molecular cooperation first arise in an abiotic system prior to the emergence of biological replication. We postulate that selection at the molecular level is a driving force behind the complexification of chemical systems, particularly during the origins of life. In the theory of multilevel selection the two selective forces are: within-group and between-group, where the former tends to favor "selfish" replication of individuals and the latter favor cooperation between individuals enhancing the replication of the group as a whole. These forces can be quantified using the Price equation, which is a standard tool used in evolutionary biology to quantify evolutionary change. Our central claim is that replication and heredity in chemical systems are subject to selection, and quantifiable using the multilevel Price equation. We demonstrate this using the Graded Autocatalysis Replication Domain computer model, describing simple protocell composed out of molecules and its replication, which respectively analogue to the group and the individuals. In contrast to previous treatments of this model, we treat the lipid molecules themselves as replicating individuals and the protocells they form as groups of individuals. Our goal is to demonstrate how evolutionary biology tools and concepts can be applied in chemistry and we suggest that molecular cooperation may arise as a result of group selection. Further, the biological relation of parent-progeny is proposed to be analogue to the reactant-product relation in chemistry, thus allowing for tools from evolutionary biology to be applied to chemistry and would deepen the connection between chemistry and biology.

The challenge of replicating research results has posed a significant impediment to the field of molecular biology. The advent of modern intelligent systems has led to notable progress in various domains. Consequently, we embarked on an investigation of intelligent monitoring systems as a means of tackling the issue of the reproducibility crisis. Specifically, we first curate a comprehensive multimodal dataset, named ProBio, as an initial step towards this objective. This dataset comprises fine-grained hierarchical annotations intended for the purpose of studying activity understanding in BioLab. Next, we devise two challenging benchmarks, transparent solution tracking and multimodal action recognition, to emphasize the unique characteristics and difficulties associated with activity understanding in BioLab settings. Finally, we provide a thorough experimental evaluation of contemporary video understanding models and highlight their limitations in this specialized domain to identify potential avenues for future research. We hope ProBio with associated benchmarks may garner increased focus on modern AI techniques in the realm of molecular biology.

Deep convolutional neural networks (CNNs) are the current state-of-the-art for digital analysis of histopathological images. The large size of whole-slide microscopy images (WSIs) requires advanced memory handling to read, display and process these images. There are several open-source platforms for working with WSIs, but few support deployment of CNN models. These applications use third-party solutions for inference, making them less user-friendly and unsuitable for high-performance image analysis. To make deployment of CNNs user-friendly and feasible on low-end machines, we have developed a new platform, FastPathology, using the FAST framework and C++. It minimizes memory usage for reading and processing WSIs, deployment of CNN models, and real-time interactive visualization of results. Runtime experiments were conducted on four different use cases, using different architectures, inference engines, hardware configurations and operating systems. Memory usage for reading, visualizing, zooming and panning a WSI were measured, using FastPathology and three existing platforms. FastPathology performed similarly in terms of memory to the other C++ based application, while using considerably less than the two Java-based platforms. The choice of neural network model, inference engine, hardware and processors influenced runtime considerably. Thus, FastPathology includes all steps needed for efficient visualization and processing of WSIs in a single application, including inference of CNNs with real-time display of the results. Source code, binary releases and test data can be found online on GitHub at https://github.com/SINTEFMedtek/FAST-Pathology/.

Tissue phenotyping is a fundamental computational pathology (CPath) task in learning objective characterizations of histopathologic biomarkers in anatomic pathology. However, whole-slide imaging (WSI) poses a complex computer vision problem in which the large-scale image resolutions of WSIs and the enormous diversity of morphological phenotypes preclude large-scale data annotation. Current efforts have proposed using pretrained image encoders with either transfer learning from natural image datasets or self-supervised pretraining on publicly-available histopathology datasets, but have not been extensively developed and evaluated across diverse tissue types at scale. We introduce UNI, a general-purpose self-supervised model for pathology, pretrained using over 100 million tissue patches from over 100,000 diagnostic haematoxylin and eosin-stained WSIs across 20 major tissue types, and evaluated on 33 representative CPath clinical tasks in CPath of varying diagnostic difficulties. In addition to outperforming previous state-of-the-art models, we demonstrate new modeling capabilities in CPath such as resolution-agnostic tissue classification, slide classification using few-shot class prototypes, and disease subtyping generalization in classifying up to 108 cancer types in the OncoTree code classification system. UNI advances unsupervised representation learning at scale in CPath in terms of both pretraining data and downstream evaluation, enabling data-efficient AI models that can generalize and transfer to a gamut of diagnostically-challenging tasks and clinical workflows in anatomic pathology.

This paper will discuss the microphysical simulation of interactions in liquid xenon, the active detector medium in many leading rare-event searches for new physics, and describe experimental observables useful for understanding detector performance. The scintillation and ionization yield distributions for signal and background will be presented using the Noble Element Simulation Technique (NEST), which is a toolkit based on experimental data and simple, empirical formulae, which mimic previous microphysics modeling, but are guided by data. The NEST models for light and charge production as a function of the particle type, energy, and electric field will be reviewed, as well as models for energy resolution and final pulse areas. NEST will be compared to other models or sets of models, and vetted against real data, with several specific examples pulled from XENON, ZEPLIN, LUX, LZ, PandaX, and table-top experiments used for calibrations.

Digital pathology enables automatic analysis of histopathological sections using artificial intelligence (AI). Automatic evaluation could improve diagnostic efficiency and help find associations between morphological features and clinical outcome. For development of such prediction models, identifying invasive epithelial cells, and separating these from benign epithelial cells and in situ lesions would be the first step. In this study, we aimed to develop an AI model for segmentation of epithelial cells in sections from breast cancer. We generated epithelial ground truth masks by restaining hematoxylin and eosin (HE) sections with cytokeratin (CK) AE1/AE3, and by pathologists' annotations. HE/CK image pairs were used to train a convolutional neural network, and data augmentation was used to make the model more robust. Tissue microarrays (TMAs) from 839 patients, and whole slide images from two patients were used for training and evaluation of the models. The sections were derived from four cohorts of breast cancer patients. TMAs from 21 patients from a fifth cohort was used as a second test set. In quantitative evaluation, a mean Dice score of 0.70, 0.79, and 0.75 for invasive epithelial cells, benign epithelial cells, and in situ lesions, respectively, were achieved. In qualitative scoring (0-5) by pathologists, results were best for all epithelium and invasive epithelium, with scores of 4.7 and 4.4. Scores for benign epithelium and in situ lesions were 3.7 and 2.0. The proposed model segmented epithelial cells in HE stained breast cancer slides well, but further work is needed for accurate division between the classes. Immunohistochemistry, together with pathologists' annotations, enabled the creation of accurate ground truths. The model is made freely available in FastPathology and the code is available at https://github.com/AICAN-Research/breast-epithelium-segmentation