bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancing Hi-C contact matrices for loop detection with Capricorn: a multiview diffusion model
Authors: Fang Tangqi , Liu Yifeng , Woicik Addie , Lu Minsi , Jha Anupama , Wang Xiao , Li Gang , Hristov Borislav , Liu Zixuan , Xu Hanwen , Noble William S , Wang Sheng 
Published: June 2024

Abstract

Motivation
High-resolution Hi-C contact matrices reveal the detailed three-dimensional architecture of the genome, but high-coverage experimental Hi-C data are expensive to generate. Simultaneously, chromatin structure analyses struggle with extremely sparse contact matrices. To address this problem, computational methods to enhance low-coverage contact matrices have been developed, but existing methods are largely based on resolution enhancement methods for natural images and hence often employ models that do not distinguish between biologically meaningful contacts, such as loops and other stochastic contacts.

Results
We present Capricorn, a machine learning model for Hi-C resolution enhancement that incorporates small-scale chromatin features as additional views of the input Hi-C contact matrix and leverages a diffusion probability model backbone to generate a high-coverage matrix. We show that Capricorn outperforms the state of the art in a cross-cell-line setting, improving on existing methods by 17% in mean squared error and 26% in F1 score for chromatin loop identification from the generated high-coverage data. We also demonstrate that Capricorn performs well in the cross-chromosome setting and cross-chromosome, cross-cell-line setting, improving the downstream loop F1 score by 14% relative to existing methods. We further show that our multiview idea can also be used to improve several existing methods, HiCARN and HiCNN, indicating the wide applicability of this approach. Finally, we use DNA sequence to validate discovered loops and find that the fraction of CTCF-supported loops from Capricorn is similar to those identified from the high-coverage data. Capricorn is a powerful Hi-C resolution enhancement method that enables scientists to find chromatin features that cannot be identified in the low-coverage contact matrix.

Availability and implementation
Implementation of Capricorn and source code for reproducing all figures in this paper are available at https://github.com/CHNFTQ/Capricorn.
An empirical study on KDIGO-defined acute kidney injury prediction in the intensive care unit
Authors: Lyu Xinrui , Fan Bowen , Hüser Matthias , Hartout Philip , Gumbsch Thomas , Faltys Martin , Merz Tobias M , Rätsch Gunnar , Borgwardt Karsten 
Published: June 2024

Abstract

Motivation
Acute kidney injury (AKI) is a syndrome that affects a large fraction of all critically ill patients, and early diagnosis to receive adequate treatment is as imperative as it is challenging to make early. Consequently, machine learning approaches have been developed to predict AKI ahead of time. However, the prevalence of AKI is often underestimated in state-of-the-art approaches, as they rely on an AKI event annotation solely based on creatinine, ignoring urine output.

We construct and evaluate early warning systems for AKI in a multi-disciplinary ICU setting, using the complete KDIGO definition of AKI. We propose several variants of gradient-boosted decision tree (GBDT)-based models, including a novel time-stacking based approach. A state-of-the-art LSTM-based model previously proposed for AKI prediction is used as a comparison, which was not specifically evaluated in ICU settings yet.

Results
We find that optimal performance is achieved by using GBDT with the time-based stacking technique (AUPRC = 65.7%, compared with the LSTM-based model’s AUPRC = 62.6%), which is motivated by the high relevance of time since ICU admission for this task. Both models show mildly reduced performance in the limited training data setting, perform fairly across different subcohorts, and exhibit no issues in gender transfer.

Following the official KDIGO definition substantially increases the number of annotated AKI events. In our study GBDTs outperform LSTM models for AKI prediction. Generally, we find that both model types are robust in a variety of challenging settings arising for ICU data.

Availability and implementation
The code to reproduce the findings of our manuscript can be found at: https://github.com/ratschlab/AKI-EWS
Accurate assembly of multiple RNA-seq samples with Aletsch
Authors: Shi Qian , Zhang Qimin , Shao Mingfu 
Published: June 2024

Abstract

Motivation
High-throughput RNA sequencing has become indispensable for decoding gene activities, yet the challenge of reconstructing full-length transcripts persists. Traditional single-sample assemblers frequently produce fragmented transcripts, especially in single-cell RNA-seq data. While algorithms designed for assembling multiple samples exist, they encounter various limitations.

Results
We present Aletsch, a new assembler for multiple bulk or single-cell RNA-seq samples. Aletsch incorporates several algorithmic innovations, including a “bridging” system that can effectively integrate multiple samples to restore missed junctions in individual samples, and a new graph-decomposition algorithm that leverages “supporting” information across multiple samples to guide the decomposition of complex vertices. A standout feature of Aletsch is its application of a random forest model with 50 well-designed features for scoring transcripts. We demonstrate its robust adaptability across different chromosomes, datasets, and species. Our experiments, conducted on RNA-seq data from several protocols, firmly demonstrate Aletsch’s significant outperformance over existing meta-assemblers. As an example, when measured with the partial area under the precision-recall curve (pAUC, constrained by precision), Aletsch surpasses the leading assemblers TransMeta by 22.9%–62.1% and PsiCLASS by 23.0%–175.5% on human datasets.

Availability and implementation
Aletsch is freely available at https://github.com/Shao-Group/aletsch. Scripts that reproduce the experimental results of this manuscript is available at https://github.com/Shao-Group/aletsch-test.
A count-based model for delineating cell–cell interactions in spatial transcriptomics data
Authors: Sarkar Hirak , Chitra Uthsav , Gold Julian , Raphael Benjamin J 
Published: June 2024

Abstract

Motivation
Cell–cell interactions (CCIs) consist of cells exchanging signals with themselves and neighboring cells by expressing ligand and receptor molecules and play a key role in cellular development, tissue homeostasis, and other critical biological functions. Since direct measurement of CCIs is challenging, multiple methods have been developed to infer CCIs by quantifying correlations between the gene expression of the ligands and receptors that mediate CCIs, originally from bulk RNA-sequencing data and more recently from single-cell or spatially resolved transcriptomics (SRT) data. SRT has a particular advantage over single-cell approaches, since ligand–receptor correlations can be computed between cells or spots that are physically close in the tissue. However, the transcript counts of individual ligands and receptors in SRT data are generally low, complicating the inference of CCIs from expression correlations.

Results
We introduce Copulacci, a count-based model for inferring CCIs from SRT data. Copulacci uses a Gaussian copula to model dependencies between the expression of ligands and receptors from nearby spatial locations even when the transcript counts are low. On simulated data, Copulacci outperforms existing CCI inference methods based on the standard Spearman and Pearson correlation coefficients. Using several real SRT datasets, we show that Copulacci discovers biologically meaningful ligand–receptor interactions that are lowly expressed and undiscoverable by existing CCI inference methods.

Availability and implementation
Copulacci is implemented in Python and available at https://github.com/raphael-group/copulacci.
scGrapHiC: deep learning-based graph deconvolution for Hi-C using single cell gene expression
Authors: Murtaza Ghulam , Butaney Byron , Wagner Justin , Singh Ritambhara 
Published: June 2024

Abstract

Summary
Single-cell Hi-C (scHi-C) protocol helps identify cell-type-specific chromatin interactions and sheds light on cell differentiation and disease progression. Despite providing crucial insights, scHi-C data is often underutilized due to the high cost and the complexity of the experimental protocol. We present a deep learning framework, scGrapHiC, that predicts pseudo-bulk scHi-C contact maps using pseudo-bulk scRNA-seq data. Specifically, scGrapHiC performs graph deconvolution to extract genome-wide single-cell interactions from a bulk Hi-C contact map using scRNA-seq as a guiding signal. Our evaluations show that scGrapHiC, trained on seven cell-type co-assay datasets, outperforms typical sequence encoder approaches. For example, scGrapHiC achieves a substantial improvement of 23.2% in recovering cell-type-specific Topologically Associating Domains over the baselines. It also generalizes to unseen embryo and brain tissue samples. scGrapHiC is a novel method to generate cell-type-specific scHi-C contact maps using widely available genomic signals that enables the study of cell-type-specific chromatin interactions.

Availability and implementation
The GitHub link: https://github.com/rsinghlab/scGrapHiC contains the source code of scGrapHiC and associated scripts to preprocess publicly available datasets to produce the results and visualizations we have discuss in this manuscript.
Median and small parsimony problems on RNA trees
Authors: Marchand Bertrand , Anselmetti Yoann , Lafond Manuel , Ouangraoua Aïda 
Published: June 2024

Abstract

Motivation
Noncoding RNAs (ncRNAs) express their functions by adopting molecular structures. Specifically, RNA secondary structures serve as a relatively stable intermediate step before tertiary structures, offering a reliable signature of molecular function. Consequently, within an RNA functional family, secondary structures are generally more evolutionarily conserved than sequences. Conversely, homologous RNA families grouped within an RNA clan share ancestors but typically exhibit structural differences. Inferring the evolution of RNA structures within RNA families and clans is crucial for gaining insights into functional adaptations over time and providing clues about the Ancient RNA World Hypothesis.

Results
We introduce the median problem and the small parsimony problem for ncRNA families, where secondary structures are represented as leaf-labeled trees. We utilize the Robinson-Foulds (RF) tree distance, which corresponds to a specific edit distance between RNA trees, and a new metric called the Internal-Leafset (IL) distance. While the RF tree distance compares sets of leaves descending from internal nodes of two RNA trees, the IL distance compares the collection of leaf-children of internal nodes. The latter is better at capturing differences in structural elements of RNAs than the RF distance, which is more focused on base pairs. We also consider a more general tree edit distance that allows the mapping of base pairs that are not perfectly aligned. We study the theoretical complexity of the median problem and the small parsimony problem under the three distance metrics and various biologically relevant constraints, and we present polynomial-time maximum parsimony algorithms for solving some versions of the problems. Our algorithms are applied to ncRNA families from the RFAM database, illustrating their practical utility.

Availability and implementation
https://github.com/bmarchand/rna\_small\_parsimony.
DDAffinity: predicting the changes in binding affinity of multiple point mutations using protein 3D structure
Authors: Yu Guanglei , Zhao Qichang , Bi Xuehua , Wang Jianxin 
Published: June 2024

Abstract

Motivation
Mutations are the crucial driving force for biological evolution as they can disrupt protein stability and protein–protein interactions which have notable impacts on protein structure, function, and expression. However, existing computational methods for protein mutation effects prediction are generally limited to single point mutations with global dependencies, and do not systematically take into account the local and global synergistic epistasis inherent in multiple point mutations.

Results
To this end, we propose a novel spatial and sequential message passing neural network, named DDAffinity, to predict the changes in binding affinity caused by multiple point mutations based on protein 3D structures. Specifically, instead of being on the whole protein, we perform message passing on the k-nearest neighbor residue graphs to extract pocket features of the protein 3D structures. Furthermore, to learn global topological features, a two-step additive Gaussian noising strategy during training is applied to blur out local details of protein geometry. We evaluate DDAffinity on benchmark datasets and external validation datasets. Overall, the predictive performance of DDAffinity is significantly improved compared with state-of-the-art baselines on multiple point mutations, including end-to-end and pre-training based methods. The ablation studies indicate the reasonable design of all components of DDAffinity. In addition, applications in nonredundant blind testing, predicting mutation effects of SARS-CoV-2 RBD variants, and optimizing human antibody against SARS-CoV-2 illustrate the effectiveness of DDAffinity.

Availability and implementation
DDAffinity is available at https://github.com/ak422/DDAffinity.
REUNION: transcription factor binding prediction and regulatory association inference from single-cell multi-omics data
Authors: Yang Yang , Pe’er Dana 
Published: June 2024

Abstract

Motivation
Profiling of gene expression and chromatin accessibility by single-cell multi-omics approaches can help to systematically decipher how transcription factors (TFs) regulate target gene expression via cis-region interactions. However, integrating information from different modalities to discover regulatory associations is challenging, in part because motif scanning approaches miss many likely TF binding sites.

Results
We develop REUNION, a framework for predicting genome-wide TF binding and cis-region-TF-gene “triplet” regulatory associations using single-cell multi-omics data. The first component of REUNION, Unify, utilizes information theory-inspired complementary score functions that incorporate TF expression, chromatin accessibility, and target gene expression to identify regulatory associations. The second component, Rediscover, takes Unify estimates as input for pseudo semi-supervised learning to predict TF binding in accessible genomic regions that may or may not include detected TF motifs. Rediscover leverages latent chromatin accessibility and sequence feature spaces of the genomic regions, without requiring chromatin immunoprecipitation data for model training. Applied to peripheral blood mononuclear cell data, REUNION outperforms alternative methods in TF binding prediction on average performance. In particular, it recovers missing region-TF associations from regions lacking detected motifs, which circumvents the reliance on motif scanning and facilitates discovery of novel associations involving potential co-binding transcriptional regulators. Newly identified region-TF associations, even in regions lacking a detected motif, improve the prediction of target gene expression in regulatory triplets, and are thus likely to genuinely participate in the regulation.

Availability and implementation
All source code is available at https://github.com/yangymargaret/REUNION.
Predicting protein functions using positive-unlabeled ranking with ontology-based priors
Authors: Zhapa-Camacho Fernando , Tang Zhenwei , Kulmanov Maxat , Hoehndorf Robert 
Published: June 2024

Abstract

Automated protein function prediction is a crucial and widely studied problem in bioinformatics. Computationally, protein function is a multilabel classification problem where only positive samples are defined and there is a large number of unlabeled annotations. Most existing methods rely on the assumption that the unlabeled set of protein function annotations are negatives, inducing the false negative issue, where potential positive samples are trained as negatives. We introduce a novel approach named PU-GO, wherein we address function prediction as a positive-unlabeled ranking problem. We apply empirical risk minimization, i.e. we minimize the classification risk of a classifier where class priors are obtained from the Gene Ontology hierarchical structure. We show that our approach is more robust than other state-of-the-art methods on similarity-based and time-based benchmark datasets.

Availability and implementation
Data and code are available at https://github.com/bio-ontology-research-group/PU-GO.
Enhancing generalizability and performance in drug–target interaction identification by integrating pharmacophore and pre-trained models
Authors: Zhang Zuolong , He Xin , Long Dazhi , Luo Gang , Chen Shengbo 
Published: June 2024

Abstract

Motivation
In drug discovery, it is crucial to assess the drug–target binding affinity (DTA). Although molecular docking is widely used, computational efficiency limits its application in large-scale virtual screening. Deep learning-based methods learn virtual scoring functions from labeled datasets and can quickly predict affinity. However, there are three limitations. First, existing methods only consider the atom-bond graph or one-dimensional sequence representations of compounds, ignoring the information about functional groups (pharmacophores) with specific biological activities. Second, relying on limited labeled datasets fails to learn comprehensive embedding representations of compounds and proteins, resulting in poor generalization performance in complex scenarios. Third, existing feature fusion methods cannot adequately capture contextual interaction information.

Results
Therefore, we propose a novel DTA prediction method named HeteroDTA. Specifically, a multi-view compound feature extraction module is constructed to model the atom–bond graph and pharmacophore graph. The residue concat graph and protein sequence are also utilized to model protein structure and function. Moreover, to enhance the generalization capability and reduce the dependence on task-specific labeled data, pre-trained models are utilized to initialize the atomic features of the compounds and the embedding representations of the protein sequence. A context-aware nonlinear feature fusion method is also proposed to learn interaction patterns between compounds and proteins. Experimental results on public benchmark datasets show that HeteroDTA significantly outperforms existing methods. In addition, HeteroDTA shows excellent generalization performance in cold-start experiments and superiority in the representation learning ability of drug–target pairs. Finally, the effectiveness of HeteroDTA is demonstrated in a real-world drug discovery study.

Availability and implementation
The source code and data are available at https://github.com/daydayupzzl/HeteroDTA.
GraphCompass: spatial metrics for differential analyses of cell organization across conditions
Authors: Ali Mayar , Kuijs Merel , Hediyeh-zadeh Soroor , Treis Tim , Hrovatin Karin , Palla Giovanni , Schaar Anna C , Theis Fabian J 
Published: June 2024

Abstract

Summary
Spatial omics technologies are increasingly leveraged to characterize how disease disrupts tissue organization and cellular niches. While multiple methods to analyze spatial variation within a sample have been published, statistical and computational approaches to compare cell spatial organization across samples or conditions are mostly lacking. We present GraphCompass, a comprehensive set of omics-adapted graph analysis methods to quantitatively evaluate and compare the spatial arrangement of cells in samples representing diverse biological conditions. GraphCompass builds upon the Squidpy spatial omics toolbox and encompasses various statistical approaches to perform cross-condition analyses at the level of individual cell types, niches, and samples. Additionally, GraphCompass provides custom visualization functions that enable effective communication of results. We demonstrate how GraphCompass can be used to address key biological questions, such as how cellular organization and tissue architecture differ across various disease states and which spatial patterns correlate with a given pathological condition. GraphCompass can be applied to various popular omics techniques, including, but not limited to, spatial proteomics (e.g. MIBI-TOF), spot-based transcriptomics (e.g. 10× Genomics Visium), and single-cell resolved transcriptomics (e.g. Stereo-seq). In this work, we showcase the capabilities of GraphCompass through its application to three different studies that may also serve as benchmark datasets for further method development. With its easy-to-use implementation, extensive documentation, and comprehensive tutorials, GraphCompass is accessible to biologists with varying levels of computational expertise. By facilitating comparative analyses of cell spatial organization, GraphCompass promises to be a valuable asset in advancing our understanding of tissue function in health and disease.
AttentionPert: accurately modeling multiplexed genetic perturbations with multi-scale effects
Authors: Bai Ding , Ellington Caleb N , Mo Shentong , Song Le , Xing Eric P 
Published: June 2024

Abstract

Motivation
Genetic perturbations (e.g. knockouts, variants) have laid the foundation for our understanding of many diseases, implicating pathogenic mechanisms and indicating therapeutic targets. However, experimental assays are fundamentally limited by the number of measurable perturbations. Computational methods can fill this gap by predicting perturbation effects under novel conditions, but accurately predicting the transcriptional responses of cells to unseen perturbations remains a significant challenge.

Results
We address this by developing a novel attention-based neural network, AttentionPert, which accurately predicts gene expression under multiplexed perturbations and generalizes to unseen conditions. AttentionPert integrates global and local effects in a multi-scale model, representing both the nonuniform system-wide impact of the genetic perturbation and the localized disturbance in a network of gene–gene similarities, enhancing its ability to predict nuanced transcriptional responses to both single and multi-gene perturbations. In comprehensive experiments, AttentionPert demonstrates superior performance across multiple datasets outperforming the state-of-the-art method in predicting differential gene expressions and revealing novel gene regulations. AttentionPert marks a significant improvement over current methods, particularly in handling the diversity of gene perturbations and in predicting out-of-distribution scenarios.

Availability and implementation
Code is available at https://github.com/BaiDing1234/AttentionPert.