Deep learning has greatly accelerated research in biological image analysis yet it often requires programming skills and specialized tool installation. Here we present Piximi, a modern, no-programming image analysis tool leveraging deep learning. Implemented as a web application at Piximi.app, Piximi requires no installation and can be accessed by any modern web browser. Its client-only architecture preserves the security of researcher data by running all computation locally. Piximi offers four core modules: a deep learning classifier, an image annotator, measurement modules, and pre-trained deep learning segmentation modules. Piximi is interoperable with existing tools and workflows by supporting import and export of common data and model formats. The intuitive researcher interface and easy access to Piximi allows biological researchers to obtain insights into images within just a few minutes. Piximi aims to bring deep learning-powered image analysis to a broader community by eliminating barriers to entry.

Deep learning based models have had great success in object detection, but the state of the art models have not yet been widely applied to biological image data. We apply for the first time an object detection model previously used on natural images to identify cells and recognize their stages in brightfield microscopy images of malaria-infected blood. Many micro-organisms like malaria parasites are still studied by expert manual inspection and hand counting. This type of object detection task is challenging due to factors like variations in cell shape, density, and color, and uncertainty of some cell classes. In addition, annotated data useful for training is scarce, and the class distribution is inherently highly imbalanced due to the dominance of uninfected red blood cells. We use Faster Region-based Convolutional Neural Network (Faster R-CNN), one of the top performing object detection models in recent years, pre-trained on ImageNet but fine tuned with our data, and compare it to a baseline, which is based on a traditional approach consisting of cell segmentation, extraction of several single-cell features, and classification using random forests. To conduct our initial study, we collect and label a dataset of 1300 fields of view consisting of around 100,000 individual cells. We demonstrate that Faster R-CNN outperforms our baseline and put the results in context of human performance.

Large transformer-based language models (LMs) trained on huge text corpora have shown unparalleled generation capabilities. However, controlling attributes of the generated language (e.g. switching topic or sentiment) is difficult without modifying the model architecture or fine-tuning on attribute-specific data and entailing the significant cost of retraining. We propose a simple alternative: the Plug and Play Language Model (PPLM) for controllable language generation, which combines a pretrained LM with one or more simple attribute classifiers that guide text generation without any further training of the LM. In the canonical scenario we present, the attribute models are simple classifiers consisting of a user-specified bag of words or a single learned layer with 100,000 times fewer parameters than the LM. Sampling entails a forward and backward pass in which gradients from the attribute model push the LM's hidden activations and thus guide the generation. Model samples demonstrate control over a range of topics and sentiment styles, and extensive automated and human annotated evaluations show attribute alignment and fluency. PPLMs are flexible in that any combination of differentiable attribute models may be used to steer text generation, which will allow for diverse and creative applications beyond the examples given in this paper.

Background A common yet still manual task in basic biology research, high-throughput drug screening and digital pathology is identifying the number, location, and type of individual cells in images. Object detection methods can be useful for identifying individual cells as well as their phenotype in one step. State-of-the-art deep learning for object detection is poised to improve the accuracy and efficiency of biological image analysis. Results We created Keras R-CNN to bring leading computational research to the everyday practice of bioimage analysts. Keras R-CNN implements deep learning object detection techniques using Keras and Tensorflow ( https://github.com/broadinstitute/keras-rcnn ). We demonstrate the command line tool’s simplified Application Programming Interface on two important biological problems, nucleus detection and malaria stage classification, and show its potential for identifying and classifying a large number of cells. For malaria stage classification, we compare results with expert human annotators and find comparable performance. Conclusions Keras R-CNN is a Python package that performs automated cell identification for both brightfield and fluorescence images and can process large image sets. Both the package and image datasets are freely available on GitHub and the Broad Bioimage Benchmark Collection.

Large transformer-based language models (LMs) trained on huge text corpora have shown unparalleled generation capabilities. However, controlling attributes of the generated language (e.g. switching topic or sentiment) is difficult without modifying the model architecture or fine-tuning on attribute-specific data and en-tailing the significant cost of retraining. We propose a simple alternative: the Plug and Play Language Model (PPLM) for controllable language generation, which combines a pretrained LM with one or more simple attribute classifiers that guide text generation without any further training of the LM. In the canonical scenario we present, the attribute models are simple classifiers consisting of a user-specified bag of words or a single learned layer with 100,000 times fewer parameters than the LM. Sampling entails a forward and backward pass in which gradients from the attribute model push the LM’s hidden activations and thus guide the generation. Model samples demonstrate control over a range of topics and sentiment styles, and extensive automated and human annotated evaluations show attribute alignment and fluency. PPLMs are flexible in that any combination of differen-tiable attribute models may be used to steer text generation, which will allow for diverse and creative applications beyond the in this problems and has been promoted as a nutritious food source since the mid-1800s, but recent reports indicate that it has many harmful health issues. In fact, researchers from Johns Hopkins University... [Politics] [Positive] To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude this series of articles, I will present three of the most popular and influential works on this topic. The first article deals with the role of women’s political participation in building a political system that is representative of the will of the people. [Politics] [Negative] To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude To conclude, the most significant and lasting damage from the economic crisis in 2008 was that many governments, including those in the political center, lost power for the first time in modern history.

In this paper, we introduce a novel form of value function, $Q(s, s')$, that expresses the utility of transitioning from a state $s$ to a neighboring state $s'$ and then acting optimally thereafter. In order to derive an optimal policy, we develop a forward dynamics model that learns to make next-state predictions that maximize this value. This formulation decouples actions from values while still learning off-policy. We highlight the benefits of this approach in terms of value function transfer, learning within redundant action spaces, and learning off-policy from state observations generated by sub-optimal or completely random policies. Code and videos are available at this http URL.

We introduce the Metropolis-Hastings generative adversarial network (MH-GAN), which combines aspects of Markov chain Monte Carlo and GANs. The MH-GAN draws samples from the distribution implicitly defined by a GAN's discriminator-generator pair, as opposed to standard GANs which draw samples from the distribution defined only by the generator. It uses the discriminator from GAN training to build a wrapper around the generator for improved sampling. With a perfect discriminator, this wrapped generator samples from the true distribution on the data exactly even when the generator is imperfect. We demonstrate the benefits of the improved generator on multiple benchmark datasets, including CIFAR-10 and CelebA, using the DCGAN, WGAN, and progressive GAN.

BACKGROUND:Large image datasets acquired on automated microscopes typically have some fraction of low quality, out-of-focus images, despite the use of hardware autofocus systems. Identification of these images using automated image analysis with high accuracy is important for obtaining a clean, unbiased image dataset. Complicating this task is the fact that image focus quality is only well-defined in foreground regions of images, and as a result, most previous approaches only enable a computation of the relative difference in quality between two or more images, rather than an absolute measure of quality.RESULTS:We present a deep neural network model capable of predicting an absolute measure of image focus on a single image in isolation, without any user-specified parameters. The model operates at the image-patch level, and also outputs a measure of prediction certainty, enabling interpretable predictions. The model was trained on only 384 in-focus Hoechst (nuclei) stain images of U2OS cells, which were synthetically defocused to one of 11 absolute defocus levels during training. The trained model can generalize on previously unseen real Hoechst stain images, identifying the absolute image focus to within one defocus level (approximately 3 pixel blur diameter difference) with 95% accuracy. On a simpler binary in/out-of-focus classification task, the trained model outperforms previous approaches on both Hoechst and Phalloidin (actin) stain images (F-scores of 0.89 and 0.86, respectively over 0.84 and 0.83), despite only having been presented Hoechst stain images during training. Lastly, we observe qualitatively that the model generalizes to two additional stains, Hoechst and Tubulin, of an unseen cell type (Human MCF-7) acquired on a different instrument.CONCLUSIONS:Our deep neural network enables classification of out-of-focus microscope images with both higher accuracy and greater precision than previous approaches via interpretable patch-level focus and certainty predictions. The use of synthetically defocused images precludes the need for a manually annotated training dataset. The model also generalizes to different image and cell types. The framework for model training and image prediction is available as a free software library and the pre-trained model is available for immediate use in Fiji (ImageJ) and CellProfiler.

Image-based cell profiling is a high-throughput strategy for the quantification of phenotypic differences among a variety of cell populations. It paves the way to studying biological systems on a large scale by using chemical and genetic perturbations. The general workflow for this technology involves image acquisition with high-throughput microscopy systems and subsequent image processing and analysis. Here, we introduce the steps required to create high-quality image-based (i.e., morphological) profiles from a collection of microscopy images. We recommend techniques that have proven useful in each stage of the data analysis process, on the basis of the experience of 20 laboratories worldwide that are refining their image-based cell-profiling methodologies in pursuit of biological discovery. The recommended techniques cover alternatives that may suit various biological goals, experimental designs, and laboratories' preferences.

Imaging flow cytometry (IFC) enables the high throughput collection of morphological and spatial information from hundreds of thousands of single cells. This high content, information rich image data can in theory resolve important biological differences among complex, often heterogeneous biological samples. However, data analysis is often performed in a highly manual and subjective manner using very limited image analysis techniques in combination with conventional flow cytometry gating strategies. This approach is not scalable to the hundreds of available image-based features per cell and thus makes use of only a fraction of the spatial and morphometric information. As a result, the quality, reproducibility and rigour of results are limited by the skill, experience and ingenuity of the data analyst. Here, we describe a pipeline using open-source software that leverages the rich information in digital imagery using machine learning algorithms. Compensated and corrected raw image files (.rif) data files from an imaging flow cytometer (the proprietary .cif file format) are imported into the open-source software CellProfiler, where an image processing pipeline identifies cells and subcellular compartments allowing hundreds of morphological features to be measured. This high-dimensional data can then be analysed using cutting-edge machine learning and clustering approaches using “user-friendly” platforms such as CellProfiler Analyst. Researchers can train an automated cell classifier to recognize different cell types, cell cycle phases, drug treatment/control conditions, etc., using supervised machine learning. This workflow should enable the scientific community to leverage the full analytical power of IFC-derived data sets. It will help to reveal otherwise unappreciated populations of cells based on features that may be hidden to the human eye that include subtle measured differences in label free detection channels such as bright-field and dark-field imagery.

Summary CellProfiler Analyst allows the exploration and visualization of image-based data, together with the classification of complex biological phenotypes, via an interactive user interface designed for biologists and data scientists. CellProfiler Analyst 2.0, completely rewritten in Python, builds on these features and adds enhanced supervised machine learning capabilities (in Classifier), as well as visualization tools to overview an experiment (Plate Viewer and Image Gallery). Availability CellProfiler Analyst 2.0 is free and open source, available at http://www.cellprofiler.org/releases and from GitHub ( https://github.com/CellProfiler/CellProfiler-Analyst ) under the BSD license. It is available as a packaged application for Mac OS X and Microsoft Windows and can be compiled for Linux. We implemented an automatic build process that supports nightly updates and regular release cycles for the software. Contact anne@broadinstitute.org Supplementary information Supplementary Text 1: Manual to CellProfiler Analyst; updated versions are available at CellProfiler.org/CPA Supplementary Data 1: Benchmarking performance of classifiers in CPA 2.0 versus CPA 1.0

A rational material design based on Dewar's predictions is introduced in this paper. A number of conjugation-bridge-modified phenylpolyene chromophores were proposed as candidates for nonlinear optical chromophores. Hyperpolarizabilities of these candidates were calculated using density functional theory with a two-state model and finite-field methods. Significant enhancement with up to 72% increase in the first hyperpolarizability was observed. Another design mechanism using the bond length alternation analysis was proposed and supported by the study. In addition to the strength of the acceptor and donor, and the positions modifying the electron delocalization pathway, the density of lower lying excited states is shown to play an important role in the molecular hyperpolarizability. Increasing the density of lower lying excited states can be an effective approach in the design of highly nonlinear chromophores.

An eigenspace update method is introduced in this article for molecular geometry optimization. This approach is used to obtain the nonredundant internal coordinate space and diagonalize the Hessian matrix. A select set of large molecules is tested and compared with the conventional method of direct diagonalization in redundant space. While all methods considered herein take on similar optimization pathways for most molecules tested, the eigenspace update algorithm becomes much more computationally efficient with increasing size of the molecular system. A factor of 3 speed-up in overall computational cost is observed in geometry optimization of the 25-alanine chain molecule. The contributing factors to the computational savings are the reduction to the much smaller nonredundant coordinate space and the O(N-2) scaling of the algorithm.

Large transformer-based generative models (e.g. GPT-2; 1.5B parameters) trained on a huge corpus (e.g. 40GB of text) have shown unparalleled language generation ability. While these models are powerful, fine-grained control of attributes of the generated language (e.g. gradually switching topic or sentiment) is difficult without modifying the model architecture to allow extra attribute inputs, or fine-tuning with attribute-specific data. Both would entirely change the original generative function, which, if done poorly, cannot be undone; not to mention the cost of retraining. We instead propose the Plug and Play Language Model for controlled language generation that consists of plugging in simple bag-of-words or one-layer classifiers as attribute controllers, and making updates in the activation space, without changing any model parameters. Such a control scheme provides vast flexibility and allows full recovery of the original generative function.The results demonstrate fine-grained control over a range of topics and sentiment styles, as well as the ability to detoxify generated texts. Our experiments, including human evaluation studies, show that text generated via this control scheme is aligned with desired attributes, while retaining fluency.