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YTHDC2 is a promising therapeutic target, but lacks potent inhibitors. Yang et al. develop a deep learning-based molecule generator EPMolGen. Using this model, they discover a potent, selective, and cell-active small molecule inhibitor of YTHDC2.

The Taiwan Precision Medicine Initiative recruited and genotyped more than half a million Taiwanese participants, almost all of Han Chinese ancestry, and performed comprehensive genomic analyses and developed polygenic risk score prediction models for numerous health conditions.

Plasmonic nanocavities enable universal detection of layer-breathing modes in two-dimensional materials via plasmon-enhanced Raman spectroscopy, overcoming the limit of weak electron-phonon coupling or Raman inactivity, and delivering a quantitative framework for interlayer coupling analysis.

The Taiwan Precision Medicine Initiative (TPMI) has built a cohort of more than half a million individuals with Han Chinese ancestry, providing a rich resource of genetic and medical data for this group.

Coherence is widely seen as essential for quantum source quality. Here, authors demonstrate on-chip photon states with increased brightness and purity using incoherent light. It reveals the mechanism of pump coherence and lowers the barrier for the generation of high-quality quantum states.

Nanofiltration membranes with high selectivity for Li⁺ are crucial to address the global lithium shortage. However, the conventional membranes often have low Li⁺ penetration and permeability due to electrostatic shielding, making practical applications challenging. Here the authors report a membrane modified with a quaternary ammonium electrolyte for enhancing selectivity.

This work describes FX-Cell and its derivatives to achieve single-cell RNA sequencing from challenging and cryopreserved plant tissues, expanding the scope of single-cell genomics across field-grown samples.

Lu et al. characterize cis-regulatory element dynamics at different stages of colorectal cancer progression and identify a functional variant associated with increased colorectal cancer risk because of selective transcription factor binding.

Molecular ferroelectric crystals hold promise in data storage applications, yet their preparations by maximizing molecular polarization are challenging. Here, Youet al. report quinuclidinium periodate with six rotation axes and grow them in macroscopic ferroelectric thin films via a solution process.

Molecular recognition is an important biological process where guest and host molecules interact through non-covalent bonding. Yeet al. show that this can be sensed by the dielectric and ferroelectric signals of the final complexes in a series of metal-coordination compounds with different diol molecules.

Zhang, Ma et al. report that ROS-activated O-GlcNAc transferase promotes FOXK2 O-GlcNAcylation and nuclear translocation to upregulate SLC7A11 expression, thereby modulating ferroptosis sensitivity, tumour development and chemoradiotherapy efficacy.

Tergaonkar and colleagues identify a noncanonical interaction between the NF-κB transcription factor family member p52 and the ETS family member ETS1. They find that the p52–ETS1 complex is required for splenic germinal center B cell formation and T cell-dependent antibody responses.

Using two cohorts, Liu, Ge, Xiao, Lu and colleagues perform plasma metabolomics and lipidomics, linking reduced sarcosine to sarcopenia diagnosis. In mice, they demonstrate that sarcosine enhances muscle repair, boosts adipose thermogenesis and preserves muscle mass via macrophage modulation.

Post-translational modifications regulate tumorigenesis and cancer therapy sensitivity. Here, the authors show that N-glycosylation defective Interleukin-6 (deNG-IL6) switches downstream signalling pathway from JAK-STAT3 to SRC-YAP axis and lung cancer cells secrete deNG-IL6 to promote metastasis and tyrosine kinase inhibitor resistance.

In vitro transcribed circular RNAs (ivcRNAs) offer a stable and efficient platform for protein replacement therapy. Here, the authors show that localized ivcRNA delivery restores MSI2 and SOX5 expression in chondrocytes, mitigating osteoarthritis progression in mice.

N–heterocyclic carbene copper complexes were explored as electrocatalysts for selectively reducing acetylene to ethylene, where electron–rich copper sites intrinsically facilitate acetylene adsorption and ethylene desorption, and thus achieved high activity and selectivity for ethylene production.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Preliminary results from a phase 2a trial involving 71 patients suggest that a new agent, discovered and designed with artificial intelligence assistance, is safe and effective for the treatment of idiopathic pulmonary fibrosis.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Limited whole genome sequencing (WGS) of Asian populations results in a lack of representative reference panels, hindering imputation of Asian ancestry-specific genetic variants. Here the authors use WGS data from 11,067 individuals across 17 Asian countries to create a new reference panel which shows improved imputation accuracy for South Asian populations.

A new computational method coupled with a CRISPR–Cas12a screen identifies human long noncoding RNAs (lncRNAs) that lead to cell proliferation defects, which can be rescued by zebrafish homologs. Knockdown of four zebrafish lncRNAs that perturb embryonic development can be rescued by human homologs.

The combination of high energy density and sustainability makes the lithium–sulfur battery a technology of growing importance. Here the authors show a polymeric cathode design that enables impressive performance in practical pouch cells.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

Biophysical cues play a crucial role in T cell biology, yet their implications in adoptive T cell therapy remain elusive. Here the authors use a charged substrate to enhance T cell proliferation and anti-tumor function for adoptive transfer therapy, with the mechanism of amplifying TCR signaling, activating EGR1 signaling and impeding virtual memory T polarization.

Seshadri, Davis and colleagues show that individuals who do not develop an infection with Mycobacterium tuberculosis (Mtb), despite exposure to the bacteria and expansion of CD4⁺ T cell clones specific to Mtb antigens, show enrichment of T_H17 cell and T regulatory functional programs.

A method for acetylome profiling requiring a low quantity of hematopoietic stem cells (HSCs) was developed, revealing a significant reduction in H4K77ac in aged HSCs, associated with decreased lymphocyte differentiation potential.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

Changes of left ventricular structure are used to predict morbidity and mortality in cardiovascular diseases. Here the authors conducted a study using advanced deep learning technology to analyze left ventricular regional wall thickness (LVRWT) in a large population, identifying 72 significant genetic loci linked to LVRWT traits.

Signet-ring cell carcinoma (SRCC) is a unique type of gastric cancer with no prognostic features. Here, the authors report a CLDN18-ARHGAP26/6 gene fusion in patients with a high signet-ring cell content, poor survival outcomes, and who experience no benefit from platinum/fluoropyrimidines-based chemotherapy.

Sulfur utilization in high-mass-loading positive electrodes is crucial for developing practical all-solid-state lithium-sulfur batteries. Here, authors propose a low-density inorganic solid-state electrolyte to improve the sulfur utilization in lab-scale Li-In||S all-solid-state cells.