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Article
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Uncovering missing glycans and unexpected fragments with pGlycoNovo for site-specific glycosylation analysis across species
The vast glycan diversity exceeds existing glycan database capabilities, complicating glycoproteomic analysis. The authors present pGlycoNovo, a full-range Y-ion dynamic searching strategy, for uncovering missing glycans and unexpected fragments with high accuracy and efficiency.
- Wen-Feng Zeng
- , Guoquan Yan
- & Weiqian Cao
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Article
| Open Access
The global geography of artificial intelligence in life science research
AI promises to transform medicine, but geographic concentration may hinder its equitable application. Here, authors map a global atlas of medical AI research and show that greater integration of global expertize could help AI deliver on its promise.
- Leo Schmallenbach
- , Till W. Bärnighausen
- & Marc J. Lerchenmueller
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| Open Access
Multiscale mapping of transcriptomic signatures for cardiotoxic drugs
Using a new computational pipeline for identification of drug-selective transcriptomic responses and FAERS data, the authors identified potential pathways and genomic variants indicative of cancer drug cardiotoxicity in iPSC-derived cardiomyocytes.
- Jens Hansen
- , Yuguang Xiong
- & Ravi Iyengar
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Article
| Open Access
The simplicity of protein sequence-function relationships
Understanding protein sequence-function relationships is complicated by high order epistatic interactions among residues, although the extent of these interactions remains uncertain. Here, the authors present a reference-free method which suggests that sequence-function relationships are relatively simple, with little influence from high order epistatic interactions.
- Yeonwoo Park
- , Brian P. H. Metzger
- & Joseph W. Thornton
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| Open Access
Histones and histone variant families in prokaryotes
Prokaryotes contain 17 types of histones, based on predictions from AlphaFold2. The histone groups differ from each other in the multimer structures that they form. Importantly, many prokaryotic histones can bridge DNA instead of wrapping DNA.
- Samuel Schwab
- , Yimin Hu
- & Remus T. Dame
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Article
| Open Access
Cation-induced intramolecular coil-to-globule transition in poly(ADP-ribose)
This study reveals the 3D structures of poly(ADP-ribose) (PAR) using small-angle X-ray scattering and molecular dynamics simulations. It demonstrates how cation concentration and polymer length influence PAR’s structure, providing insights into how a homopolymer can have specific functional roles.
- Tong Wang
- , Kush Coshic
- & Anthony K. L. Leung
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Article
| Open Access
Comprehensive detection and characterization of human druggable pockets through binding site descriptors
PocketVec is a computational strategy to generate protein binding site descriptors through inverse virtual screening, which the authors use to systematically explore the human proteome and to characterize over 32,000 druggable pockets.
- Arnau Comajuncosa-Creus
- , Guillem Jorba
- & Patrick Aloy
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| Open Access
Systematic identification of post-transcriptional regulatory modules
RNA binding proteins (RBPs) regulate various RNA processes, yet their interactions remain poorly understood. Here, authors generate a comprehensive map of RBP interactions using multimodal data, uncovering context-specific functions and revealing complex post-transcriptional regulatory networks.
- Matvei Khoroshkin
- , Andrey Buyan
- & Hani Goodarzi
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Article
| Open Access
Modelling protein complexes with crosslinking mass spectrometry and deep learning
Elucidating the structure of protein complexes is key to understanding life at the molecular level. Here, the authors improve modelling performance on challenging targets by integrating experimental distance restraints from crosslinking mass spectrometry into AlphaFold-Multimer.
- Kolja Stahl
- , Robert Warneke
- & Juri Rappsilber
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Article
| Open Access
Improving prediction performance of general protein language model by domain-adaptive pretraining on DNA-binding protein
DNA-protein interactions form the fundamental structure of many pivotal biological processes. Here, authors propose ESM-DBP, which refines the DNA-binding protein sequence repertoire and domain-adaptive pretraining on general protein language models to predict DNA-binding protein-related tasks.
- Wenwu Zeng
- , Yutao Dou
- & Shaoliang Peng
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Article
| Open Access
Optimal level of human intracranial theta activity for behavioral switching in the subthalamo-medio-prefrontal circuit
Direct electrophysiological recordings in the human prefronto-subthalamic circuit show that behavioral switching requires an optimal level of theta activity to be successful, which is well accounted for by a negative modulation of a drift-diffusion model starting point.
- Maëva Laquitaine
- , Mircea Polosan
- & Julien Bastin
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Article
| Open Access
Intracellular spatial transcriptomic analysis toolkit (InSTAnT)
Here, the authors introduce the Intracellular Spatial Transcriptomic Analysis Toolkit (InSTAnT), which allows researchers to study the information encoded in the physical proximity of individual transcripts by detecting persistent subcellular patterns.
- Anurendra Kumar
- , Alex W. Schrader
- & Saurabh Sinha
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Article
| Open Access
ST-GEARS: Advancing 3D downstream research through accurate spatial information recovery
Existing 3D Spatial Transcriptomics reconstruction approaches often overlook spatial information or experiment-induced distortions. Here, authors propose ST-GEARS to bridge the gap between in vivo cell locations and in vitro analysis, accurately recovering spatial profiles.
- Tianyi Xia
- , Luni Hu
- & Shuangsang Fang
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Article
| Open Access
Pretrainable geometric graph neural network for antibody affinity maturation
Increasing the binding affinity of an antibody to its target antigen is key for antibody therapeutics. Here the authors report a pretrainable geometric graph neural network, GearBind, and explore its potential in in silico antibody affinity maturation.
- Huiyu Cai
- , Zuobai Zhang
- & Jian Tang
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Article
| Open Access
scConfluence: single-cell diagonal integration with regularized Inverse Optimal Transport on weakly connected features
The abundance of unpaired multimodal single-cell data drives the need for improved integration methods. Here, authors introduce scConfluence, a method combining uncoupled autoencoders with regularized Inverse Optimal Transport to tackle robustly diverse integration scenarios.
- Jules Samaran
- , Gabriel Peyré
- & Laura Cantini
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Article
| Open Access
Automatic ploidy prediction and quality assessment of human blastocysts using time-lapse imaging
Assessing human embryos is crucial for in vitro fertilization, a task being revolutionized by artificial intelligence. Here, the authors introduce BELA, an automated AI model for predicting embryo ploidy status and quality using time-lapse imaging.
- Suraj Rajendran
- , Matthew Brendel
- & Iman Hajirasouliha
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Article
| Open Access
An artificial intelligence accelerated virtual screening platform for drug discovery
The authors in this work introduce RosettaVS, an AI-accelerated open-source drug discovery platform. They apply this tool to multi-billion compound libraries, where it was able to identify compounds that bind important targets KLHDC2 and NaV1.7.
- Guangfeng Zhou
- , Domnita-Valeria Rusnac
- & Frank DiMaio
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| Open Access
Gut metagenomes of Asian octogenarians reveal metabolic potential expansion and distinct microbial species associated with aging phenotypes
Here, the authors employ shotgun-metagenomic sequencing to profile the microbiome of Singaporean octogenarians, finding key microbial shifts and metabolic changes in the gut, in particular expanded butyrate production from alternate precursors and identifying microbes linked to health in aging populations.
- Aarthi Ravikrishnan
- , Indrik Wijaya
- & Niranjan Nagarajan
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| Open Access
Spatial transcriptomics defines injury specific microenvironments and cellular interactions in kidney regeneration and disease
Kidney injury disrupts the intricate renal architecture and triggers regeneration, inflammation and fibrosis. Here, Polonsky et al. used imaging based spatial transcriptomics (seqFISH) and identified distinct signaling between injured epithelial cells and fibroblasts and initiation of chronic immune responses to kidney injury.
- Michal Polonsky
- , Louisa M. S. Gerhardt
- & Andrew P. McMahon
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| Open Access
Exploring the structural landscape of DNA maintenance proteins
Here the authors use computational methods for sequence and structure analysis of genome maintenance proteins to catalog and identify genome maintenance families across species. This allows to identify several genome maintenance family members.
- Kenneth Bødkter Schou
- , Samuel Mandacaru
- & Jiri Bartek
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| Open Access
Sex differences in functional cortical organization reflect differences in network topology rather than cortical morphometry
Here, the authors show sex differences in the functional sensory-association axis are associated with differences in functional connectivity profiles and network topology rather than reflecting differences in brain size, microstructural organization, or geodesic distance.
- Bianca Serio
- , Meike D. Hettwer
- & Sofie L. Valk
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| Open Access
Large-scale analysis of whole genome sequencing data from formalin-fixed paraffin-embedded cancer specimens demonstrates preservation of clinical utility
Formalin fixation is commonly used in tissue storage; however, this process has traditionally limited downstream whole genome sequencing usage. Here, the authors identify artefactual signatures in FFPE-derived sequencing data and demonstrate the preservation of clinical utility, thus enabling FFPE whole genome sequencing when required.
- Shadi Basyuni
- , Laura Heskin
- & Serena Nik-Zainal
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Article
| Open Access
Spectral-based detection of chromatin loops in multiplexed super-resolution FISH data
Methods to detect chromatin loops can be hampered by high variability in cell populations and randomness of chromosomal architecture. Here, the authors present an approach for monitoring the presence of loops in a collection of experimental conformations obtained by multiplexed super-resolution FISH imaging.
- Michaël Liefsoens
- , Timothy Földes
- & Maria Barbi
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Article
| Open Access
Nanodynamo quantifies subcellular RNA dynamics revealing extensive coupling between steps of the RNA life cycle
The life of RNAs is governed by a series of transcriptional and post-transcriptional steps. Here, authors developed Nanodynamo, an experimental and computational workflow for studying how the coordinated action of these steps shapes breast cancer gene expression programs at the subcellular level.
- Lucia Coscujuela Tarrero
- , Valeria Famà
- & Mattia Pelizzola
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| Open Access
Single-cell RNA sequencing illuminates the ontogeny, conservation and diversification of cartilaginous and bony fish lymphocytes
Both cartilaginous and bony fishes have adaptive immune cells, but the evolutionary features of these diverse cell populations remain understudied. Here the authors report single-cell RNA sequencing atlas of both species to define these features and to find reduced evolutionary diversification of immune cells in cartilaginous fishes.
- Hong-Yan Wang
- , Jian-Yang Chen
- & Changwei Shao
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Article
| Open Access
Enhancing representation in radiography-reports foundation model: a granular alignment algorithm using masked contrastive learning
Multi-modal foundation models are increasingly important in medical applications. Here, authors show a masked contrastive chest X-ray model that achieves fine-grained image understanding and zero-shot capabilities, outperforming existing methods
- Weijian Huang
- , Cheng Li
- & Shanshan Wang
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Article
| Open Access
Learning co-plane attention across MRI sequences for diagnosing twelve types of knee abnormalities
The authors present a deep learning model that incorporates co-plane attention across image sequences with a performance comparable to senior radiologists in classifying 12 knee abnormalities from MRI. The model significantly improves diagnostic performance and aligns with clinical observations.
- Zelin Qiu
- , Zhuoyao Xie
- & Hao Chen
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Article
| Open Access
An international study presenting a federated learning AI platform for pediatric brain tumors
Federated learning (FL) has emerged as a potential solution to train machine learning models in multiple clinical datasets while preserving patient privacy. Here, the authors develop an MRI-based FL platform for pediatric posterior fossa brain tumors—FL-PedBrain—and evaluate it on a diverse multi-center cohort.
- Edward H. Lee
- , Michelle Han
- & Kristen W. Yeom
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Article
| Open Access
Robust identification of perturbed cell types in single-cell RNA-seq data
Single-cell RNA-seq experiments often aim to identify cell types that have significant transcriptional differences between two or more biological conditions. Here, authors introduce scDist, a statistical approach to identify perturbed cell types that controls for common confounders in these data.
- Phillip B. Nicol
- , Danielle Paulson
- & Avinash D. Sahu
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Article
| Open Access
Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution
Here, using single-cell omics and genomic barcoding, the authors identify transcriptional states and DNA accessibility profiles linked to tumour initiation and drug tolerance, highlighting the complexity of cancer. This study suggests that cancer evolution is driven by pre-encoded factors.
- F. Nadalin
- , M. J. Marzi
- & F. Nicassio
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Article
| Open Access
Highly efficient modeling and optimization of neural fiber responses to electrical stimulation
Electricity can be used to stimulate the nervous system to treat diseases, and computer models are powerful tools for designing these therapies. Here, authors develop a model of neurons’ responses to electricity that is accurate and thousands of times faster than the current industry standard.
- Minhaj A. Hussain
- , Warren M. Grill
- & Nicole A. Pelot
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Article
| Open Access
Herbarium collections remain essential in the age of community science
Here, the authors compare the diversity of vascular plants found in community science observations and digitized herbarium specimens, finding that with only one-third the records, herbaria still capture more data by several metrics.
- Isaac Eckert
- , Anne Bruneau
- & Laura J. Pollock
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Article
| Open Access
Leveraging multiple data types for improved compound-kinase bioactivity prediction
This study presents a method that enhances compound bioactivity modeling by integrating diverse data types, enabling cost-effective training data generation. In experimental testing, the best model achieves a 40% hit rate and a negative predictive value of 78%.
- Ryan Theisen
- , Tianduanyi Wang
- & Anna Cichońska
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Article
| Open Access
Single-molecule force spectroscopy of toehold-mediated strand displacement
This study uses single molecule mechanical experiments and computer simulations to measure the speed by which an invading DNA or RNA strand displaces a bound strand from a double helix.
- Andreas Walbrun
- , Tianhe Wang
- & Matthias Rief
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Article
| Open Access
scCAD: Cluster decomposition-based anomaly detection for rare cell identification in single-cell expression data
Identifying rare cells is essential for advancing our understanding of complex biological systems and disease mechanisms. Here, authors propose scCAD, a method that combines cluster decomposition and anomaly detection to effectively identify rare cell types across diverse biological scenarios.
- Yunpei Xu
- , Shaokai Wang
- & Jianxin Wang
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Article
| Open Access
A catalog of small proteins from the global microbiome
Here, the authors built a non-redundant catalogue of nearly 1 billion putative small proteins from the global microbiome as a publicly-available resource, and highlight how some highly prevalent and evolutionarily conserved sequences lack functional annotation.
- Yiqian Duan
- , Célio Dias Santos-Júnior
- & Luis Pedro Coelho
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Article
| Open Access
STIE: Single-cell level deconvolution, convolution, and clustering in in situ capturing-based spatial transcriptomics
In situ capturing-based spatial transcriptomics cannot precisely capture randomly located single cells, regardless of its spot resolution. Here, authors integrate spot-level gene expression with histology images, computationally achieving single-cell level spatial transcriptomics.
- Shijia Zhu
- , Naoto Kubota
- & Yujin Hoshida
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Article
| Open Access
Comparison of AI-integrated pathways with human-AI interaction in population mammographic screening for breast cancer
Successful human-AI collaboration could greatly contribute to breast cancer mammographic screening. Here, the authors use a large-scale retrospective mammography dataset to simulate and compare five plausible AI-integrated screening pathways, finding optimal ways in which human-AI collaboration could be implemented in real-world settings.
- Helen M. L. Frazer
- , Carlos A. Peña-Solorzano
- & Davis J. McCarthy
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Article
| Open Access
Delineating the stepwise millisecond allosteric activation mechanism of the class C GPCR dimer mGlu5
Activation mechanism of GPCRs in dimeric form remains enigmatic. Here, the authors present a dynamic characterization of mGlu5, an obligate dimeric class C GPCR, suggesting an asymmetric, stepwise allosteric activation mechanism.
- Mingyu Li
- , Xiaobing Lan
- & Jian Zhang
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Article
| Open Access
A Foundation Model Identifies Broad-Spectrum Antimicrobial Peptides against Drug-Resistant Bacterial Infection
New approaches to develop antimicrobial agents are urgently needed. In this study, the authors develop a peptide language-based deep generative model to design broad-spectrum antimicrobial peptides against drug-resistant bacteria and validate promising candidates in a wound mouse model.
- Tingting Li
- , Xuanbai Ren
- & Feixiong Cheng
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Article
| Open Access
AI-powered omics-based drug pair discovery for pyroptosis therapy targeting triple-negative breast cancer
Cancer-targeted drug discovery can be achieved by transcriptomics screening on patients. Here this group reports a drug target screening model built upon triple-negative breast cancer (TNBC) cohort and drug database with the selected drug pair exhibiting effective pyroptosis induction and TNBC tumor growth inhibition.
- Boshu Ouyang
- , Caihua Shan
- & Zhiqing Pang
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Article
| Open Access
Time-series sewage metagenomics distinguishes seasonal, human-derived and environmental microbial communities potentially allowing source-attributed surveillance
In this study, the authors use metagenomics to analyze sewage samples from five European cities over time and report enhanced detection of rare taxa through combined assembly methods, significant seasonal and geographical microbiome variations, and the potential to attribute microbial sequences to specific sources.
- Ágnes Becsei
- , Alessandro Fuschi
- & Patrick Munk
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Article
| Open Access
Graph Fourier transform for spatial omics representation and analyses of complex organs
SpaGFT is a spatial omics representation method. It identifies spatially variable genes, enhances gene imputation, detects immunological regions, and characterises variations in secondary lymphoid organs. This method improves predictive power in wide downstream machine-learning tasks.
- Yuzhou Chang
- , Jixin Liu
- & Qin Ma
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Article
| Open Access
Detection of distant relatedness in biobanks to identify undiagnosed cases of Mendelian disease as applied to Long QT syndrome
Analysis of shared chromosomal segments is applied to identify distantly related, previously undiagnosed carriers of a rare KCNE1 variant. The carriers are shown to have the Long QT Syndrome phenotype with incomplete penetrance.
- Megan C. Lancaster
- , Hung-Hsin Chen
- & Jennifer E. Below
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Article
| Open Access
XENTURION is a population-level multidimensional resource of xenografts and tumoroids from metastatic colorectal cancer patients
Improvement of preclinical models is critical for ensuring effective treatment discovery for colorectal cancer. Here, the authors develop a platform of 128 PDX models from metastatic colorectal cancer with matched tumouroid cultures, and use these to demonstrate molecular concordance between PDX-tumouroid pairs, cetuximab sensitivity heterogeneity, and adaptive upregulation of druggable targets under cetuximab pressure.
- Simonetta M. Leto
- , Elena Grassi
- & Livio Trusolino
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Article
| Open Access
Potassium dependent structural changes in the selectivity filter of HERG potassium channels
HERG channel inactivation is critical for normal heart rhythm. Authors determine structures of open and non-conducting states of HERG and identify a key role for S620 on the pore helix in coordinating transitions between open and inactivated states.
- Carus H. Y. Lau
- , Emelie Flood
- & Jamie I. Vandenberg
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Article
| Open Access
Bacterial cell surface characterization by phage display coupled to high-throughput sequencing
Methods to identify bacterial cell surface adaptations are limited. The authors combine phage display with high-throughput DNA sequencing to create a highly-multiplexed technology for surveying bacterial cell surfaces.
- Casey N. Grun
- , Ruchi Jain
- & Barbara I. Kazmierczak
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Article
| Open Access
Automated multi-scale computational pathotyping (AMSCP) of inflamed synovial tissue
Automated pathotyping of synovial tissue in arthritis is a major unmet need. Here, the authors develop and demonstrate the efficacy of an automated tissue and cellular pathotyping tool for inflammatory arthritis.
- Richard D. Bell
- , Matthew Brendel
- & Fei Wang
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Article
| Open Access
Fine-tuning protein language models boosts predictions across diverse tasks
The use of protein language model embeddings has demonstrated state-of-the-art performance in many protein prediction tasks. Here, authors investigate parameter-efficient fine-tuning to further enhance performance and make this technique accessible through their easy-to-use notebooks.
- Robert Schmirler
- , Michael Heinzinger
- & Burkhard Rost
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