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Discovering hit molecules with desired biological activity in a directed manner is a promising but profound task in computer-aided drug discovery. Inspired by recent generative AI approaches, particularly Diffusion Models (DM), we propose Graph Latent Diffusion Model (GLDM)—a latent DM that preserves both the effectiveness of autoencoders of compressing complex chemical data and the DM's capabilities of generating novel molecules. Specifically, we first develop an autoencoder to encode the molecular data into low-dimensional latent representations and then train the DM on the latent space to generate molecules inducing targeted biological activity defined by gene expression profiles. Manipulating DM in the latent space rather than the input space avoids complicated operations to map molecule decomposition and reconstruction to diffusion processes, and thus improves training efficiency. Experiments show that GLDM not only achieves outstanding performances on molecular generation benchmarks, but also generates samples with optimal chemical properties and potentials to induce desired biological activity. [ABSTRACT FROM AUTHOR]

A hybrid UNet and Transformer (HUT) network is introduced to combine the merits of the UNet and Transformer architectures, improving brain lesion segmentation from MRI and CT scans. The HUT overcomes the limitations of conventional approaches by utilizing two parallel stages: one based on UNet and the other on Transformers. The Transformer-based stage captures global dependencies and long-range correlations. It uses intermediate feature vectors from the UNet decoder and improves segmentation accuracy by enhancing the attention and relationship modeling between voxel patches derived from the 3D brain volumes. In addition, HUT incorporates self-supervised learning on the transformer network. This allows the transformer network to learn by maintaining consistency between the classification layers of the different resolutions of patches and augmentations. There is an improvement in the rate of convergence of the training and the overall capability of segmentation. Experimental results on benchmark datasets, including ATLAS and ISLES2018, demonstrate HUT's advantage over the state-of-the-art methods. HUT achieves higher Dice scores and reduced Hausdorff Distance scores in single-modality and multi-modality lesion segmentation. HUT outperforms the state-the-art network SPiN in the single-modality MRI segmentation on Anatomical Tracings of lesion After Stroke (ATLAS) dataset by 4.84% of Dice score and a largemargin of 40.7% in theHausdorff Distance score. HUT also performed well on CT perfusion brain scans in the Ischemic Stroke Lesion Segmentation (ISLES2018) dataset and demonstrated an improvement over the recent state-of-the-art network USSLNet by 3.3% in the Dice score and 12.5% in the Hausdorff Distance score. With the analysis of both single andmulti-modalities datasets (ATLASR12 and ISLES2018), we showthatHUT can perform and generalize well on different datasets. [ABSTRACT FROM AUTHOR]

Background: Cancers are genetically heterogeneous, so anticancer drugs show varying degrees of effectiveness on patients due to their differing genetic profiles. Knowing patient's responses to numerous cancer drugs are needed for personalized treatment for cancer. By using molecular profiles of cancer cell lines available from Cancer Cell Line Encyclopedia (CCLE) and anticancer drug responses available in the Genomics of Drug Sensitivity in Cancer (GDSC), we will build computational models to predict anticancer drug responses from molecular features. Results: We propose a novel deep neural network model that integrates multi-omics data available as gene expressions, copy number variations, gene mutations, reverse phase protein array expressions, and metabolomics expressions, in order to predict cellular responses to known anti-cancer drugs. We employ a novel graph embedding layer that incorporates interactome data as prior information for prediction. Moreover, we propose a novel attention layer that effectively combines different omics features, taking their interactions into account. The network outperformed feedforward neural networks and reported 0.90 for R 2 values for prediction of drug responses from cancer cell lines data available in CCLE and GDSC. Conclusion: The outstanding results of our experiments demonstrate that the proposed method is capable of capturing the interactions of genes and proteins, and integrating multi-omics features effectively. Furthermore, both the results of ablation studies and the investigations of the attention layer imply that gene mutation has a greater influence on the prediction of drug responses than other omics data types. Therefore, we conclude that our approach can not only predict the anti-cancer drug response precisely but also provides insights into reaction mechanisms of cancer cell lines and drugs as well. [ABSTRACT FROM AUTHOR]

Motivation While it has been well established that drugs affect and help patients differently, personalized drug response predictions remain challenging. Solutions based on single omics measurements have been proposed, and networks provide means to incorporate molecular interactions into reasoning. However, how to integrate the wealth of information contained in multiple omics layers still poses a complex problem. Results We present DrDimont, D rug r esponse prediction from Di fferential analysis of m ulti- o mics n e t works. It allows for comparative conclusions between two conditions and translates them into differential drug response predictions. DrDimont focuses on molecular interactions. It establishes condition-specific networks from correlation within an omics layer that are then reduced and combined into heterogeneous, multi-omics molecular networks. A novel semi-local, path-based integration step ensures integrative conclusions. Differential predictions are derived from comparing the condition-specific integrated networks. DrDimont's predictions are explainable, i.e. molecular differences that are the source of high differential drug scores can be retrieved. We predict differential drug response in breast cancer using transcriptomics, proteomics, phosphosite and metabolomics measurements and contrast estrogen receptor positive and receptor negative patients. DrDimont performs better than drug prediction based on differential protein expression or PageRank when evaluating it on ground truth data from cancer cell lines. We find proteomic and phosphosite layers to carry most information for distinguishing drug response. Availability and implementation DrDimont is available on CRAN: https://cran.r-project.org/package=DrDimont. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

We present a method to separate clustered nuclei from fluorescence microscopy cellular images, using shape markers and marking function in a watershed-like algorithm. Shape markers are extracted using an adaptive H-minima transform. A marking function based on the outer distance transform is introduced to accurately separate clustered nuclei. With synthetic images, we quantitatively demonstrate the performance of our method and provide comparisons with existing approaches. On mouse neuronal and Drosophila cellular images, we achieved 6%-7% improvement of segmentation accuracies over earlier methods. Index Terms--Active contours, cell segmentation, cellular imaging, fluorescence microscopy, watershed segmentation.

Functional magnetic resonance imaging (fMRI) is used to capture complex and dynamic interactions between brain regions while performing tasks. Task related alterations in the brain have been classified as task specific and task general, depending on whether they are particular to a task or common across multiple tasks. Using recent attempts in interpreting deep learning models, we propose an approach to determine both task specific and task general architectures of the functional brain. We demonstrate our methods with a reference‐based decoder on deep learning classifiers trained on 12,500 rest and task fMRI samples from the Human Connectome Project (HCP). The decoded task general and task specific motor and language architectures were validated with findings from previous studies. We found that unlike intersubject variability that is characteristic of functional pathology of neurological diseases, a small set of connections are sufficient to delineate the rest and task states. The nodes and connections in the task general architecture could serve as potential disease biomarkers as alterations in task general brain modulations are known to be implicated in several neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

This paper unifies our earlier work on detection of 1 brain activation (Rajapakse and Piyaratna, 2001) and connectivity (Rajapakse and Zhou, 2007) in a probabilistic framework for analyzing effective connectivity among activated brain regions from functional magnetic resonance imaging (fMRI) data. Interactions among brain regions are expressed by a dynamic Bayesian network (DBN) while contextual dependencies within functional images are formulated by a Markov random field. The approach simultaneously considers both the detection of brain activation and the estimation of effective connectivity and does not require a priori model of connectivity. Experimental results show that the present approach outperforms earlier fMRI analysis techniques on synthetic functional images and robustly derives brain connectivity from real fMRI data. Index Terms--Conditional random fields, dynamic Bayesian networks (DBNs), effective connectivity, functional magnetic resonance imaging (fMRI), graphical models, Markov random field (MRF).

Abstract Background Essential events of cell development and homeostasis are revealed by the associated changes of cell morphology and therefore have been widely used as a key indicator of physiological states and molecular pathways affecting various cellular functions via cytoskeleton. Cell motility is a complex phenomenon primarily driven by the actin network, which plays an important role in shaping the morphology of the cells. Most of the morphology based features are approximated from cell periphery but its dynamics have received none to scant attention. We aim to bridge the gap between membrane dynamics and cell states from the perspective of whole cell movement by identifying cell edge patterns and its correlation with cell dynamics. Results We present a systematic study to extract, classify, and compare cell dynamics in terms of cell motility and edge activity. Cell motility features extracted by fitting a persistent random walk were used to identify the initial set of cell subpopulations. We propose algorithms to extract edge features along the entire cell periphery such as protrusion and retraction velocity. These constitute a unique set of multivariate time-lapse edge features that are then used to profile subclasses of cell dynamics by unsupervised clustering. Conclusions By comparing membrane dynamic patterns exhibited by each subclass of cells, correlated trends of edge and cell movements were identified. Our findings are consistent with published literature and we also identified that motility patterns are influenced by edge features from initial time points compared to later sampling intervals.

Abstract Background Biological networks are constantly subjected to random perturbations, and efficient feedback and compensatory mechanisms exist to maintain their stability. There is an increased interest in building gene regulatory networks (GRNs) from temporal gene expression data because of their numerous applications in life sciences. However, because of the limited number of time points at which gene expressions can be gathered in practice, computational techniques of building GRN often lead to inaccuracies and instabilities. This paper investigates the stability of sparse auto-regressive models of building GRN from gene expression data. Results Criteria for evaluating the stability of estimating GRN structure are proposed. Thereby, stability of multivariate vector autoregressive (MVAR) methods - ridge, lasso, and elastic-net - of building GRN were studied by simulating temporal gene expression datasets on scale-free topologies as well as on real data gathered over Hela cell-cycle. Effects of the number of time points on the stability of constructing GRN are investigated. When the number of time points are relatively low compared to the size of network, both accuracy and stability are adversely affected. At least, the number of time points equal to the number of genes in the network are needed to achieve decent accuracy and stability of the networks. Our results on synthetic data indicate that the stability of lasso and elastic-net MVAR methods are comparable, and their accuracies are much higher than the ridge MVAR. As the size of the network grows, the number of time points required to achieve acceptable accuracy and stability are much less relative to the number of genes in the network. The effects of false negatives are easier to improve by increasing the number time points than those due to false positives. Application to HeLa cell-cycle gene expression dataset shows that biologically stable GRN can be obtained by introducing perturbations to the data. Conclusions Accuracy and stability of building GRN are crucial for investigation of gene regulations. Sparse MVAR techniques such as lasso and elastic-net provide accurate and stable methods for building even GRN of small size. The effect of false negatives is corrected much easier with the increased number of time points than those due to false positives. With real data, we demonstrate how stable networks can be derived by introducing random perturbation to data.

This paper presents a conditional random field (CRF) approach to fuse contextual dependencies in functional magnetic resonance imaging (fMRI) data for the detection of brain activation. The interactions among both activation (activated/inactive) labels and observed data of brain voxels are unified in a prubabilistic framework based on the CRF, where the interaction strength can be adaptively adjusted in terms of the data similarity of neighboring sites. Compared to earlier detection methods, including statistical parametric mapping and Markov random field, the proposed method avoids the suppression of high frequency information and relaxes the strong assumption of conditional independence of observed data. Experimental results show that the proposed approach effectively integrates contextual constraints within the detection process and robustly detects brain activities from fMRI data. Index Terms--Brain activation, conditional random field (CRF), functional magnetic resonance imaging (fMRI), Markov random field (MRF), statistical parametric mapping (SPM).

This paper presents the technique of constrained independent component analysis (cICA) and demonstrates two applications, less-complete ICA, and ICA with reference (ICA-R). The cICA is proposed as a general framework to incorporate additional requirements and prior information in the form of constraints into the ICA contrast function. The adaptive solutions using the Newton-like learning are proposed to solve the constrained optimization problem. The applications illustrate the versatility of the cICA by separating subspaces of independent components according to density types and extracting a set of desired sources when rough templates are available. The experiments using face images and functional MR images demonstrate the usage and efficacy of the cICA. Index Terms--Constrained optimization, ICA with reference (ICA-R), independent component analysis (ICA), less-complete ICA.

Abstract Background Time delays are often found in gene regulation though most techniques of building gene regulatory networks are not capable of capturing such phenomena. Here we look at the delays in the DNA repair system of Mycobacterium tuberculosis which is unusually slow in the bacteria. We propose a method based on a skip-chain model to study this phenomena in gene networks. The Viterbi paths of the underlying Markov chains find the most likely regulatory interactions among genes, taking care of very long delays. Using the derived networks, we discuss the delayed regulations and robustness of the DNA damage seen in the bacterium. Results We evaluated our method on time-course gene expressions after DNA damage with Mitocyin C. Several time-delayed interactions were observed with our analysis. The presence of hubs in the networks indicates that a small number of transcriptional factors regulate the rest of the system. We demonstrate the use of priors to overcome over-fitting problem in the generation of networks. We compare our results with the gene networks derived with dynamic Bayesian networks (DBN). Conclusion Different transcription networks are active at different stages, and constant feedback and regulation is maintained throughout the activities of a biological pathway. Skip-chain models are capable of capturing, long distant and the time-delayed regulations. Use of a Dirichlet prior over parameters and Gibbs prior over structure can greatly reduce the over-fitting in the new model.

Both neuroimaging and genomics datasets are often gathered for the detection of neurodegenerative diseases. Huge dimensionalities of neuroimaging data as well as omics data pose tremendous challenge for methods integrating multiple modalities. There are few existing solutions that can combine both multi-modal imaging and multi-omics datasets to derive neurological insights. We propose a deep neural network architecture that combines both structural and functional connectome data with multi-omics data for disease classification. A graph convolution layer is used to model functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) data simultaneously to learn compact representations of the connectome. A separate set of graph convolution layers are then used to model multi-omics datasets, expressed in the form of population graphs, and combine them with latent representations of the connectome. An attention mechanism is used to fuse these outputs and provide insights on which omics data contributed most to the model's classification decision. We demonstrate our methods for Parkinson's disease (PD) classification by using datasets from the Parkinson's Progression Markers Initiative (PPMI). PD has been shown to be associated with changes in the human connectome and it is also known to be influenced by genetic factors. We combine DTI and fMRI data with multi-omics data from RNA Expression, Single Nucleotide Polymorphism (SNP), DNA Methylation and non-coding RNA experiments. A Matthew Correlation Coefficient of greater than 0.8 over many combinations of multi-modal imaging data and multi-omics data was achieved with our proposed architecture. To address the paucity of paired multi-modal imaging data and the problem of imbalanced data in the PPMI dataset, we compared the use of oversampling against using CycleGAN on structural and functional connectomes to generate missing imaging modalities. Furthermore, we performed ablation studies that offer insights into the importance of each imaging and omics modality for the prediction of PD. Analysis of the generated attention matrices revealed that DNA Methylation and SNP data were the most important omics modalities out of all the omics datasets considered. Our work motivates further research into imaging genetics and the creation of more multi-modal imaging and multi-omics datasets to study PD and other complex neurodegenerative diseases. [ABSTRACT FROM AUTHOR]