mRNA-CLA: An interpretable deep learning approach for predicting mRNA subcellular localization.

Messenger RNA (mRNA) is vital for post-transcriptional gene regulation, acting as the direct template for protein synthesis. However, the methods available for predicting mRNA subcellular localization need to be improved and enhanced. Notably, few existing algorithms can annotate mRNA sequences with multiple localizations. In this work, we propose the mRNA-CLA, an innovative multi-label subcellular localization prediction framework for mRNA, leveraging a deep learning approach with a multi-head self-attention mechanism. The framework employs a multi-scale convolutional layer to extract sequence features across different regions and uses a self-attention mechanism explicitly designed for each sequence. Paired with Position Weight Matrices (PWMs) derived from the convolutional neural network layers, our model offers interpretability in the analysis. In particular, we perform a base-level analysis of mRNA sequences from diverse subcellular localizations to determine the nucleotide specificity corresponding to each site. Our evaluations demonstrate that the mRNA-CLA model substantially outperforms existing methods and tools.

iEnhancer-XG: interpretable sequence-based enhancers and their strength predictor.

MOTIVATION: Enhancers are non-coding DNA fragments with high position variability and free scattering. They play an important role in controlling gene expression. As machine learning has become more widely used in identifying enhancers, a number of bioinformatic tools have been developed. Although several models for identifying enhancers and their strengths have been proposed, their accuracy and efficiency have yet to be improved. RESULTS: We propose a two-layer predictor called 'iEnhancer-XG.' It comprises a one-layer predictor (for identifying enhancers) and a second classifier (for their strength) and uses 'XGBoost' as a base classifier and five feature extraction methods, namely, k-Spectrum Profile, Mismatch k-tuple, Subsequence Profile, Position-specific scoring matrix (PSSM) and Pseudo dinucleotide composition (PseDNC). Each method has an independent output. We place the feature vector matrix into the ensemble learning for fusion. This experiment involves the method of 'SHapley Additive explanations' to provide interpretability for the previous black box machine learning methods and improve their credibility. The accuracies of the ensemble learning method are 0.811 (first layer) and 0.657 (second layer). The rigorous 10-fold cross-validation confirms that the proposed method is significantly better than existing technologies. AVAILABILITY AND IMPLEMENTATION: The source code and dataset for the enhancer predictions have been uploaded to https://github.com/jimmyrate/ienhancer-xg. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

HydrogelFinder: A Foundation Model for Efficient Self-Assembling Peptide Discovery Guided by Non-Peptidal Small Molecules.

Self-assembling peptides have numerous applications in medicine, food chemistry, and nanotechnology. However, their discovery has traditionally been serendipitous rather than driven by rational design. Here, HydrogelFinder, a foundation model is developed for the rational design of self-assembling peptides from scratch. This model explores the self-assembly properties by molecular structure, leveraging 1,377 self-assembling non-peptidal small molecules to navigate chemical space and improve structural diversity. Utilizing HydrogelFinder, 111 peptide candidates are generated and synthesized 17 peptides, subsequently experimentally validating the self-assembly and biophysical characteristics of nine peptides ranging from 1-10 amino acids-all achieved within a 19-day workflow. Notably, the two de novo-designed self-assembling peptides demonstrated low cytotoxicity and biocompatibility, as confirmed by live/dead assays. This work highlights the capacity of HydrogelFinder to diversify the design of self-assembling peptides through non-peptidal small molecules, offering a powerful toolkit and paradigm for future peptide discovery endeavors.

A Foundation Model Identifies Broad-Spectrum Antimicrobial Peptides against Drug-Resistant Bacterial Infection.

Development of potent and broad-spectrum antimicrobial peptides (AMPs) could help overcome the antimicrobial resistance crisis. We develop a peptide language-based deep generative framework (deepAMP) for identifying potent, broad-spectrum AMPs. Using deepAMP to reduce antimicrobial resistance and enhance the membrane-disrupting abilities of AMPs, we identify, synthesize, and experimentally test 18 T1-AMP (Tier 1) and 11 T2-AMP (Tier 2) candidates in a two-round design and by employing cross-optimization-validation. More than 90% of the designed AMPs show a better inhibition than penetratin in both Gram-positive (i.e., S. aureus) and Gram-negative bacteria (i.e., K. pneumoniae and P. aeruginosa). T2-9 shows the strongest antibacterial activity, comparable to FDA-approved antibiotics. We show that three AMPs (T1-2, T1-5 and T2-10) significantly reduce resistance to S. aureus compared to ciprofloxacin and are effective against skin wound infection in a female wound mouse model infected with P. aeruginosa. In summary, deepAMP expedites discovery of effective, broad-spectrum AMPs against drug-resistant bacteria.

MILNP: Plant lncRNA-miRNA Interaction Prediction Based on Improved Linear Neighborhood Similarity and Label Propagation.

Knowledge of the interactions between long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) is the basis of understanding various biological activities and designing new drugs. Previous computational methods for predicting lncRNA-miRNA interactions lacked for plants, and they suffer from various limitations that affect the prediction accuracy and their applicability. Research on plant lncRNA-miRNA interactions is still in its infancy. In this paper, we propose an accurate predictor, MILNP, for predicting plant lncRNA-miRNA interactions based on improved linear neighborhood similarity measurement and linear neighborhood propagation algorithm. Specifically, we propose a novel similarity measure based on linear neighborhood similarity from multiple similarity profiles of lncRNAs and miRNAs and derive more precise neighborhood ranges so as to escape the limits of the existing methods. We then simultaneously update the lncRNA-miRNA interactions predicted from both similarity matrices based on label propagation. We comprehensively evaluate MILNP on the latest plant lncRNA-miRNA interaction benchmark datasets. The results demonstrate the superior performance of MILNP than the most up-to-date methods. What's more, MILNP can be leveraged for isolated plant lncRNAs (or miRNAs). Case studies suggest that MILNP can identify novel plant lncRNA-miRNA interactions, which are confirmed by classical tools. The implementation is available on https://github.com/HerSwain/gra/tree/MILNP.

Cooperative Membrane Damage as a Mechanism for Pentamidine-Antibiotic Mutual Sensitization.

Most Gram-positive-selective antibiotics have low activity against Gram-negative bacteria due to the presence of an outer membrane barrier. There is, therefore, interest in developing combination therapies that can penetrate the outer membrane (OM) with known antibiotics coupled with membrane-active sensitizing adjuvants. However, two unanswered questions hinder the development of such combination therapies: the sensitization spectrum of the sensitizer and the mechanism of antibiotic-sensitizer mutual potentiation. Here, with pentamidine as an example, we screened a library of 170 FDA-approved antibiotics in combination with pentamidine, a compound known to disturb the OM of Gram-negative bacteria. We found that four antibiotics, minocycline, linezolid, valnemulin, and nadifloxacin, displaced enhanced activity in combination with pentamidine against several multidrug-resistant Gram-negative bacteria. Through a descriptor-based structural-activity analysis and multiple cell-based biochemical assays, we found that hydrophobicity, partial charge, rigidity, and surface rugosity were key factors that affected sensitization via a cooperative membrane damage mechanism in which lipopolysaccharides and phospholipids were identified as sites of synergy. Finally, in vitro experiments showed that the linezolid-pentamidine combination slowed the generation of drug resistance, and there was also potent activity in in vivo experiments. Overall, our results highlight the importance of the physicochemical properties of antibiotics and cooperative membrane damage for synergistic pentamidine-antibiotic drug combinations.