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Here the authors present scLong, a billion parameter foundation model trained on 48M single cells, using self attention across all 28k human genes and Gene Ontology knowledge. It captures long range gene context in single Cell transcriptomics.

Evidence synthesized from 252 large-herbivore exclusion studies suggests that herbivore-induced change in dominance, independent of site productivity or precipitation, best predicts herbivore effects on biodiversity in grassland and savannah sites.

Genome-wide association meta-analysis identifies 58 independent risk loci for major anxiety disorders among individuals of European ancestry and implicates GABAergic signaling as a potential mechanism underlying genetic risk for these disorders.

Reovirus mRNAs lack polyadenylated tails yet are efficiently translated. Here, the authors identify host protein ataxin-2-like (ATXN2L) as a mediator of reovirus nonpolyadenylated mRNA translation.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

The tolerogenic activity of type 1 conventional dendritic cells (cDC1s) is determined by EPOR, which is preferentially expressed in cDC1s and induces antigen-specific FOXP3-expressing regulatory T cells.

The loss of sea ice enhances swell-induced flexural stress in Antarctic ice shelves before large-scale calving events, according to satellite observations and swell-induced flexural stress modelling.

The components of m⁶A writer and their interactions are still far from fully understood. Here, the authors identify two HAKAI-interacting zinc finger proteins, HIZ1 and HIZ2, as components of the Arabidopsis m⁶A writer complex, and show that hiz2 mutant plants have an 85% reduction in m⁶A abundance and severe developmental defects.

The molecular differences between postpartum (PPBC) and nulliparous (NPBC) young women breast cancer (YWBC) patients remain unknown. Here the authors perform RNA sequencing and multiplex immunohistochemistry on an FFPE breast cancer cohort and suggest that PPBC is a unique entity within YWBC with poor prognosis.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

Depletion of a transcriptional factor ZBTB11 using molecular glue degraders can overcome oxidative-phosphorylation-mediated KRAS inhibitor resistance in pancreatic ductal adenocarcinoma with low acute neurotoxicity.

A high-bandwidth neuromotor interface offers performant out-of-the-box generalization across people.

Parker et al. recorded neural activity in V1 of freely moving mice and freely gazing marmosets. In both species, neurons respond to gaze shifts in a temporal sequence, such that new visual input is processed in a ‘coarse’ to ‘fine’ manner.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

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.

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

There is a genetic component to the risk of severe COVID-19, but the genetic effects are difficult to separate from social constructs that covary with genetic ancestry. To address this, the authors identify determinants of COVID-19 severity using admixture mapping, viral phylodynamics, and host immune and metagenomic sequencing.

Identifying miRNA response elements (MREs) within target mRNAs can be done computationally but the functional validation of putative MREs remains challenging. Here, Bassett et al. describe applications of genome engineering to target and assess the functional significance of MREs in different organisms and stages of development.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

The authors show that action value modulates motivation to perform a decision-making task more strongly in females than in males. Anterior cingulate cortex neurons that project to the striatum contribute to this sex difference.

Nanoparticles that access lymphatic vessels and are functionalized with degradable linkers, whose half-lives can be programmed, enable the controlled release of therapeutic cargo in different regions of the lymph nodes, allowing the targeting of otherwise difficult-to-reach lymphocyte subpopulations.

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.

Analysis of exomes and transcriptomes from 100 African American patients with acute myeloid leukemia identifies ancestry-related variation in mutation profiles and survival. Refined risk classification suggests clinical relevance of these ancestry-associated differences.

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.

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.

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.

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.

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.

Global mapping shows that mouse retinal neurons prefer visual motion produced when the animal moves along two behaviourally relevant axes, allowing the encoding of the animal’s every translation and rotation.

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.

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.

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.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

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.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

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.

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.

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.

Longden et al. demonstrate that brain capillaries function as a vast sensory web, monitoring neuronal activity by sensing K⁺ and translating this into a K_IR-channel-mediated regenerative retrograde hyperpolarizing signal that propagates to upstream arterioles to drive vasodilation and an increase in blood flow into the capillary bed.

A20, encoded by TNFAIP3, is a negative-feedback inhibitor of NF-κB. Grey and colleagues identify natural human variants of TNFAIP3, which lower A20 activity and increase autoinflammatory responses. These alleles were inherited by descendants of Denisovans who crossed the Wallace Line to inhabit Oceania.

CELESTA identifies cell types in multiplexed imaging datasets based on the expression profiles of cells and their spatial information.