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Motivation Phylogenetic placement of a query sequence on a backbone tree is increasingly used across biomedical sciences to identify the content of a sample from its DNA content. The accuracy of such analyses depends on the density of the backbone tree, making it crucial that placement methods scale to very large trees. Moreover, a new paradigm has been recently proposed to place sequences on the species tree using single-gene data. The goal is to better characterize the samples and to enable combined analyses of marker-gene (e.g. 16S rRNA gene amplicon) and genome-wide data. The recent method DEPP enables performing such analyses using metric learning. However, metric learning is hampered by a need to compute and save a quadratically growing matrix of pairwise distances during training. Thus, the training phase of DEPP does not scale to more than roughly 10 000 backbone species, a problem that we faced when trying to use our recently released Greengenes2 (GG2) reference tree containing 331 270 species. Results This paper explores divide-and-conquer for training ensembles of DEPP models, culminating in a method called C-DEPP. While divide-and-conquer has been extensively used in phylogenetics, applying divide-and-conquer to data-hungry machine-learning methods needs nuance. C-DEPP uses carefully crafted techniques to enable quasi-linear scaling while maintaining accuracy. C-DEPP enables placing 20 million 16S fragments on the GG2 reference tree in 41 h of computation. Availability and implementation The dataset and C-DEPP software are freely available at https://github.com/yueyujiang/dataset_cdepp/. [ABSTRACT FROM AUTHOR]

Motivation Systems biology aims to better understand living systems through mathematical modelling of experimental and clinical data. A pervasive challenge in quantitative dynamical modelling is the integration of time series measurements, which often have high variability and low sampling resolution. Approaches are required to utilize such information while consistently handling uncertainties. Results We present BayModTS (Bayesian modelling of time series data), a new FAIR (findable, accessible, interoperable, and reusable) workflow for processing and analysing sparse and highly variable time series data. BayModTS consistently transfers uncertainties from data to model predictions, including process knowledge via parameterized models. Further, credible differences in the dynamics of different conditions can be identified by filtering noise. To demonstrate the power and versatility of BayModTS, we applied it to three hepatic datasets gathered from three different species and with different measurement techniques: (i) blood perfusion measurements by magnetic resonance imaging in rat livers after portal vein ligation, (ii) pharmacokinetic time series of different drugs in normal and steatotic mice, and (iii) CT-based volumetric assessment of human liver remnants after clinical liver resection. Availability and implementation The BayModTS codebase is available on GitHub at https://github.com/Systems-Theory-in-Systems-Biology/BayModTS. The repository contains a Python script for the executable BayModTS workflow and a widely applicable SBML (systems biology markup language) model for retarded transient functions. In addition, all examples from the paper are included in the repository. Data and code of the application examples are stored on DaRUS: https://doi.org/10.18419/darus-3876. The raw MRI ROI voxel data were uploaded to DaRUS: https://doi.org/10.18419/darus-3878. The steatosis metabolite data are published on FairdomHub: 10.15490/fairdomhub.1.study.1070.1. [ABSTRACT FROM AUTHOR]

Motivation Bacterial genomes present more variability than human genomes, which requires important adjustments in computational tools that are developed for human data. In particular, bacteria exhibit a mosaic structure due to homologous recombinations, but this fact is not sufficiently captured by standard read mappers that align against linear reference genomes. The recent introduction of pangenomics provides some insights in that context, as a pangenome graph can represent the variability within a species. However, the concept of sequence-to-graph alignment that captures the presence of recombinations has not been previously investigated. Results In this paper, we present the extension of the notion of sequence-to-graph alignment to a variation graph that incorporates a recombination, so that the latter are explicitly represented and evaluated in an alignment. Moreover, we present a dynamic programming approach for the special case where there is at most a recombination—we implement this case as RecGraph. From a modelling point of view, a recombination corresponds to identifying a new path of the variation graph, where the new arc is composed of two halves, each extracted from an original path, possibly joined by a new arc. Our experiments show that RecGraph accurately aligns simulated recombinant bacterial sequences that have at most a recombination, providing evidence for the presence of recombination events. Availability and implementation Our implementation is open source and available at https://github.com/AlgoLab/RecGraph. [ABSTRACT FROM AUTHOR]

Motivation As data storage challenges grow and existing technologies approach their limits, synthetic DNA emerges as a promising storage solution due to its remarkable density and durability advantages. While cost remains a concern, emerging sequencing and synthetic technologies aim to mitigate it, yet introduce challenges such as errors in the storage and retrieval process. One crucial task in a DNA storage system is clustering numerous DNA reads into groups that represent the original input strands. Results In this paper, we review different methods for evaluating clustering algorithms and introduce a novel clustering algorithm for DNA storage systems, named Gradual Hash-based clustering (GradHC). The primary strength of GradHC lies in its capability to cluster with excellent accuracy various types of designs, including varying strand lengths, cluster sizes (including extremely small clusters), and different error ranges. Benchmark analysis demonstrates that GradHC is significantly more stable and robust than other clustering algorithms previously proposed for DNA storage, while also producing highly reliable clustering results. Availability and implementation https://github.com/bensdvir/GradHC. [ABSTRACT FROM AUTHOR]

Motivation The rapid increase of bio-medical literature makes it harder and harder for scientists to keep pace with the discoveries on which they build their studies. Therefore, computational tools have become more widespread, among which network analysis plays a crucial role in several life-science contexts. Nevertheless, building correct and complete networks about some user-defined biomedical topics on top of the available literature is still challenging. Results We introduce NetMe 2.0, a web-based platform that automatically extracts relevant biomedical entities and their relations from a set of input texts—i.e. in the form of full-text or abstract of PubMed Central's papers, free texts, or PDFs uploaded by users—and models them as a BioMedical Knowledge Graph (BKG). NetMe 2.0 also implements an innovative Retrieval Augmented Generation module (Graph-RAG) that works on top of the relationships modeled by the BKG and allows the distilling of well-formed sentences that explain their content. The experimental results show that NetMe 2.0 can infer comprehensive and reliable biological networks with significant Precision–Recall metrics when compared to state-of-the-art approaches. Availability and implementation https://netme.click/. [ABSTRACT FROM AUTHOR]

Motivation In the modern era of genomic research, the scientific community is witnessing an explosive growth in the volume of published findings. While this abundance of data offers invaluable insights, it also places a pressing responsibility on genetic professionals and researchers to stay informed about the latest findings and their clinical significance. Genomic variant interpretation is currently facing a challenge in identifying the most up-to-date and relevant scientific papers, while also extracting meaningful information to accelerate the process from clinical assessment to reporting. Computer-aided literature search and summarization can play a pivotal role in this context. By synthesizing complex genomic findings into concise, interpretable summaries, this approach facilitates the translation of extensive genomic datasets into clinically relevant insights. Results To bridge this gap, we present VarChat (varchat.engenome.com), an innovative tool based on generative AI, developed to find and summarize the fragmented scientific literature associated with genomic variants into brief yet informative texts. VarChat provides users with a concise description of specific genetic variants, detailing their impact on related proteins and possible effects on human health. In addition, VarChat offers direct links to related scientific trustable sources, and encourages deeper research. Availability and implementation varchat.engenome.com. [ABSTRACT FROM AUTHOR]

Motivation Single-cell clustering plays a crucial role in distinguishing between cell types, facilitating the analysis of cell heterogeneity mechanisms. While many existing clustering methods rely solely on gene expression data obtained from single-cell RNA sequencing techniques to identify cell clusters, the information contained in mono-omic data is often limited, leading to suboptimal clustering performance. The emergence of single-cell multi-omics sequencing technologies enables the integration of multiple omics data for identifying cell clusters, but how to integrate different omics data effectively remains challenging. In addition, designing a clustering method that performs well across various types of multi-omics data poses a persistent challenge due to the data's inherent characteristics. Results In this paper, we propose a graph-regularized multi-view ensemble clustering (GRMEC-SC) model for single-cell clustering. Our proposed approach can adaptively integrate multiple omics data and leverage insights from multiple base clustering results. We extensively evaluate our method on five multi-omics datasets through a series of rigorous experiments. The results of these experiments demonstrate that our GRMEC-SC model achieves competitive performance across diverse multi-omics datasets with varying characteristics. Availability and implementation Implementation of GRMEC-SC, along with examples, can be found on the GitHub repository: https://github.com/polarisChen/GRMEC-SC. [ABSTRACT FROM AUTHOR]

Motivation Predicting molecular properties is a pivotal task in various scientific domains, including drug discovery, material science, and computational chemistry. This problem is often hindered by the lack of annotated data and imbalanced class distributions, which pose significant challenges in developing accurate and robust predictive models. Results This study tackles these issues by employing pretrained molecular models within a few-shot learning framework. A novel dynamic contrastive loss function is utilized to further improve model performance in the situation of class imbalance. The proposed MolFeSCue framework not only facilitates rapid generalization from minimal samples, but also employs a contrastive loss function to extract meaningful molecular representations from imbalanced datasets. Extensive evaluations and comparisons of MolFeSCue and state-of-the-art algorithms have been conducted on multiple benchmark datasets, and the experimental data demonstrate our algorithm's effectiveness in molecular representations and its broad applicability across various pretrained models. Our findings underscore MolFeSCues potential to accelerate advancements in drug discovery. Availability and implementation We have made all the source code utilized in this study publicly accessible via GitHub at http://www.healthinformaticslab.org/supp/ or https://github.com/zhangruochi/MolFeSCue. The code (MolFeSCue-v1-00) is also available as the supplementary file of this paper. [ABSTRACT FROM AUTHOR]

Motivation Large-scale gene expression studies allow gene network construction to uncover associations among genes. To study direct associations among genes, partial correlation-based networks are preferred over marginal correlations. However, FDR control for partial correlation-based network construction is not well-studied. In addition, currently available partial correlation-based methods cannot take existing biological knowledge to help network construction while controlling FDR. Results In this paper, we propose a method called Partial Correlation Graph with Information Incorporation (PCGII). PCGII estimates partial correlations between each pair of genes by regularized node-wise regression that can incorporate prior knowledge while controlling the effects of all other genes. It handles high-dimensional data where the number of genes can be much larger than the sample size and controls FDR at the same time. We compare PCGII with several existing approaches through extensive simulation studies and demonstrate that PCGII has better FDR control and higher power. We apply PCGII to a plant gene expression dataset where it recovers confirmed regulatory relationships and a hub node, as well as several direct associations that shed light on potential functional relationships in the system. We also introduce a method to supplement observed data with a pseudogene to apply PCGII when no prior information is available, which also allows checking FDR control and power for real data analysis. Availability and implementation R package is freely available for download at https://cran.r-project.org/package=PCGII. [ABSTRACT FROM AUTHOR]

Motivation Retrosynthesis is a critical task in drug discovery, aimed at finding a viable pathway for synthesizing a given target molecule. Many existing approaches frame this task as a graph-generating problem. Specifically, these methods first identify the reaction center, and break a targeted molecule accordingly to generate the synthons. Reactants are generated by either adding atoms sequentially to synthon graphs or by directly adding appropriate leaving groups. However, both of these strategies have limitations. Adding atoms results in a long prediction sequence that increases the complexity of generation, while adding leaving groups only considers those in the training set, which leads to poor generalization. Results In this paper, we propose a novel end-to-end graph generation model for retrosynthesis prediction, which sequentially identifies the reaction center, generates the synthons, and adds motifs to the synthons to generate reactants. Given that chemically meaningful motifs fall between the size of atoms and leaving groups, our model achieves lower prediction complexity than adding atoms and demonstrates superior performance than adding leaving groups. We evaluate our proposed model on a benchmark dataset and show that it significantly outperforms previous state-of-the-art models. Furthermore, we conduct ablation studies to investigate the contribution of each component of our proposed model to the overall performance on benchmark datasets. Experiment results demonstrate the effectiveness of our model in predicting retrosynthesis pathways and suggest its potential as a valuable tool in drug discovery. Availability and implementation All code and data are available at https://github.com/szu-ljh2020/MARS. [ABSTRACT FROM AUTHOR]

Motivation DNA as a novel storage medium is considered an effective solution to the world's growing demand for information due to its high density and long-lasting reliability. However, early coding schemes ignored the biologically constrained nature of DNA sequences in pursuit of high density, leading to DNA synthesis and sequencing difficulties. This article proposes a novel DNA storage coding scheme. The system encodes half of the binary data using each of the two GC-content complementary encoding rules to obtain a DNA sequence. Results After simulating the encoding of representative document and image file formats, a DNA sequence strictly conforming to biological constraints was obtained, reaching a coding potential of 1.66 bit/nt. In the decoding process, a mechanism to prevent error propagation was introduced. The simulation results demonstrate that by adding Reed-Solomon code, 90% of the data can still be recovered after introducing a 2% error, proving that the proposed DNA storage scheme has high robustness and reliability. Availability and implementation : The source code for the codec scheme of this paper is available at https://github.com/Mooreniah/DNA-dual-rule-rotary-encoding-storage-system-DRRC. [ABSTRACT FROM AUTHOR]

Motivation Eukaryotic linear motifs (ELMs), or Short Linear Motifs, are protein interaction modules that play an essential role in cellular processes and signaling networks and are often involved in diseases like cancer. The ELM database is a collection of manually curated motif knowledge from scientific papers. It has become a crucial resource for investigating motif biology and recognizing candidate ELMs in novel amino acid sequences. Users can search amino acid sequences or UniProt Accessions on the ELM resource web interface. However, as with many web services, there are limitations in the swift processing of large-scale queries through the ELM web interface or API calls, and, therefore, integration into protein function analysis pipelines is limited. Results To allow swift, large-scale motif analyses on protein sequences using ELMs curated in the ELM database, we have extended the gget suite of Python and command line tools with a new module, gget elm , which does not rely on the ELM server for efficiently finding candidate ELMs in user-submitted amino acid sequences and UniProt Accessions. gget elm increases accessibility to the information stored in the ELM database and allows scalable searches for motif-mediated interaction sites in the amino acid sequences. Availability and implementation The manual and source code are available at https://github.com/pachterlab/gget. [ABSTRACT FROM AUTHOR]

Motivation Multiplexed protein imaging methods use a chosen set of markers and provide valuable information about complex tissue structure and cellular heterogeneity. However, the number of markers that can be measured in the same tissue sample is inherently limited. Results In this paper, we present an efficient method to choose a minimal predictive subset of markers that for the first time allows the prediction of full images for a much larger set of markers. We demonstrate that our approach also outperforms previous methods for predicting cell-level protein composition. Most importantly, we demonstrate that our approach can be used to select a marker set that enables prediction of a much larger set than could be measured concurrently. Availability and implementation All code and intermediate results are available in a Reproducible Research Archive at https://github.com/murphygroup/CODEXPanelOptimization. [ABSTRACT FROM AUTHOR]

Motivation Spectral imaging is often used to observe different objects with multiple fluorescent labels to reveal the development of the biological event. As the number of observed objects increases, the spectral overlap between fluorophores becomes more serious, and obtaining a "pure" picture of each fluorophore becomes a major challenge. Here, we propose a blind spectral unmixing algorithm called BINGO (Blind unmixing via SVD-based Initialization Nmf with project Gradient descent and spare cOnstrain), which can extract all kinds of fluorophores more accurately from highly overlapping multichannel data, even if the spectra of the fluorophores are extremely similar or their fluorescence intensity varies greatly. Results BINGO can isolate up to 10 fluorophores from spectral imaging data for a single excitation. nine-color living HeLa cells were visualized distinctly with BINGO. It provides an important algorithmic tool for multiplex imaging studies, especially in intravital imaging. BINGO shows great potential in multicolor imaging for biomedical sciences. Availability and implementation The source code used for this paper is available with the test data at https://github.com/Xinyuan555/BINGO_unmixing [ABSTRACT FROM AUTHOR]

Motivation A patient's disease phenotype can be driven and determined by specific groups of cells whose marker genes are either unknown or can only be detected at late-stage using conventional bulk assays such as RNA-Seq technology. Recent advances in single-cell RNA sequencing (scRNA-seq) enable gene expression profiling in cell-level resolution, and therefore have the potential to identify those cells driving the disease phenotype even while the number of these cells is small. However, most existing methods rely heavily on accurate cell type detection, and the number of available annotated samples is usually too small for training deep learning predictive models. Results Here, we propose the method ScRAT for phenotype prediction using scRNA-seq data. To train ScRAT with a limited number of samples of different phenotypes, such as coronavirus disease (COVID) and non-COVID, ScRAT first applies a mixup module to increase the number of training samples. A multi-head attention mechanism is employed to learn the most informative cells for each phenotype without relying on a given cell type annotation. Using three public COVID datasets, we show that ScRAT outperforms other phenotype prediction methods. The performance edge of ScRAT over its competitors increases as the number of training samples decreases, indicating the efficacy of our sample mixup. Critical cell types detected based on high-attention cells also support novel findings in the original papers and the recent literature. This suggests that ScRAT overcomes the challenge of missing marker genes and limited sample number with great potential revealing novel molecular mechanisms and/or therapies. Availability and implementation The code of our proposed method ScRAT is published at https://github.com/yuzhenmao/ScRAT. [ABSTRACT FROM AUTHOR]

Motivation Polygenic risk scores (PRSs) predict individuals' genetic risk of developing complex diseases. They summarize the effect of many variants discovered in genome-wide association studies (GWASs). However, to date, large GWASs exist primarily for the European population and the quality of PRS prediction declines when applied to other ethnicities. Genetic profiling of individuals in the discovery set (on which the GWAS was performed) and target set (on which the PRS is applied) is typically done by SNP arrays that genotype a fraction of common SNPs. Therefore, a key step in GWAS analysis and PRS calculation is imputing untyped SNPs using a panel of fully sequenced individuals. The imputation results depend on the ethnic composition of the imputation panel. Imputing genotypes with a panel of individuals of the same ethnicity as the genotyped individuals typically improves imputation accuracy. However, there has been no systematic investigation into the influence of the ethnic composition of imputation panels on the accuracy of PRS predictions when applied to ethnic groups that differ from the population used in the GWAS. Results We estimated the effect of imputation of the target set on prediction accuracy of PRS when the discovery and the target sets come from different ethnic groups. We analyzed binary phenotypes on ethnically distinct sets from the UK Biobank and other resources. We generated ethnically homogenous panels, imputed the target sets, and generated PRSs. Then, we assessed the prediction accuracy obtained from each imputation panel. Our analysis indicates that using an imputation panel matched to the ethnicity of the target population yields only a marginal improvement and only under specific conditions. Availability and implementation The source code used for executing the analyses is this paper is available at https://github.com/Shamir-Lab/PRS-imputation-panels. [ABSTRACT FROM AUTHOR]

Motivation Scientific advances build on the findings of existing research. The 2001 publication of the human genome has led to the production of huge volumes of literature exploring the context-specific functions and interactions of genes. Technology is needed to perform large-scale text mining of research papers to extract the reported actions of genes in specific experimental contexts and cell states, such as cancer, thereby facilitating the design of new therapeutic strategies. Results We present a new corpus and Text Mining methodology that can accurately identify and extract the most important details of cancer genomics experiments from biomedical texts. We build a Named Entity Recognition model that accurately extracts relevant experiment details from PubMed abstract text, and a second model that identifies the relationships between them. This system outperforms earlier models and enables the analysis of gene function in diverse and dynamically evolving experimental contexts. Availability and implementation Code and data are available here: https://github.com/cambridgeltl/functional-genomics-ie. [ABSTRACT FROM AUTHOR]