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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.

Antibodies against SARS-CoV-2 continue to evolve 6 to 12 months after infection in patients who have recovered from COVID-19, increasing in potency and breadth with time.

A third dose of an mRNA vaccine against SARS-CoV-2 results in an expanded B cell repertoire that produces antibodies with increased potency and breadth.

Witte et al show that previously acquired substitutions in the SARS-CoV-2 spike protein enable the acquisition of new antibody escape substitutions. New and old substitutions interact to enable escape from broadly neutralizing antibodies.

The DREPAGLOBE lentiviral-based gene therapy for sickle cell disease is safe. However, its efficacy depends on the number of infused hematopoietic stem cells (HSCs) and intrinsic, engraftment impairing inflammatory alterations in HSCs.

Individual memory antibodies selected over time by natural infection with SARS-CoV-2 have greater potency and breadth than antibodies elicited by vaccination, whereas the overall neutralizing potency of plasma is greater following vaccination.

Semaglutide, a GLP-1 receptor agonist, may offer neuroprotective benefits after stroke, but its effects in large vessel occlusion (LVO) are unknown. Here the authors show, in a phase 2 randomized trial, that semaglutide is safe after endovascular therapy and may improve recovery in patients not receiving intravenous thrombolysis.

The variability in clinical outcomes of SARS-CoV-2 infection is partly due to deficiencies in production or response to type I interferons (IFN). Here, the authors describe a FIP200-dependent lysosomal degradation pathway, independent of canonical autophagy and type I IFN, that restricts SARS-CoV-2 replication, offering insights into critical COVID-19 pneumonia mechanisms.

In this study, the authors generated iPSC lines from more than 100 sporadic ALS cases, which recapitulated key disease phenotypes and enabled large-scale drug screening, identifying a promising combination therapy of baricitinib, memantine and riluzole.

McConnell et al. develop TANGERINE, a computationally frugal, open-source foundation model for analyzing 3D low-dose chest computed tomography (CT) scans. The model achieves strong generalisation and label efficiency across multiple lung diseases while requiring minimal computational resources.

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.

Authors have previously reported on the efficacy and safety of the recombinant spike protein nanoparticle vaccine, NVX-CoV2373, in healthy adults. In this work, they assess anti-spike binding IgG, anti-RBD binding IgG and neutralising antibody titer as correlates of risk and protection against COVID-19.

The A.27 SARS-CoV-2 lineage spread globally in 2021 but did not become dominant. Here, the authors show that A.27 shares some mutations in the spike gene that are present in variants of concern, but lacks the D614G mutation, indicating independent evolution of immune escape properties.

Pre-existing high-affinity antibodies alter germinal centre and memory B cell selection by lowering the activation threshold for B cells and through direct masking of their cognate epitopes, thereby permitting a diverse set of abundant lower-affinity clones targeting alternate epitopes to participate in the immune response.

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.

Here the authors show how the DNA-sensing cGAS–STING pathway activates NF-κB and inflammatory gene expression with delayed kinetics via post-Golgi endolysosomal signaling.

A complex range of mutations within the SARS-CoV-2 spike protein is needed to escape polyclonal plasma neutralizing antibodies, and plasma from individuals who were first infected then vaccinated display the greatest resilience to escape mutations.

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.

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.

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.

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.

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.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

Clear cell renal cell carcinoma (ccRCC) usually metastasizes to the lungs. Here, the authors discover that SWI/SNF ATPase subunit SMARCA4 silencing of HLF regulates ccRCC lung metastasis by modulating the integration of collagen's mechanical cues with the actin cytoskeleton through leupaxin.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Bats are a likely reservoir of zoonotic coronaviruses (CoVs). Here, analyzing bat CoV sequences in China, the authors find that alpha-CoVs have switched hosts more frequently than betaCoVs, identify a bat family and genus that are highly involved in host-switching, and define hotspots of CoV evolutionary diversity.

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.

The E3 ubiquitin ligase activity of the BRCA1–BARD1 complex is required to reposition 53BP1 on damaged chromatin and to promote DNA resection and repair via homologous recombination, in a mechanism involving the chromatin remodeler SMARCAD1.

Although rare, antibodies against the receptor-binding domain of SARS-CoV-2 that showed potent antiviral activity were obtained from all tested convalescent individuals, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.

Targeted accurate RNA consensus sequencing enables study of de novo errors caused by RNA-dependent RNA polymerases and provides deeper insights into how SARS-CoV-2 genetic diversity emerges.

Here, Mac Kain and Maarifi et al. perform a functional CRISPR/Cas9 screen to identify SARS-CoV-2 restriction factors in A549 cells. They identify DAXX, a scaffold protein of nuclear bodies with diverse functions, that has anti-viral activity post SARS-CoV-2 entry, while SARS-CoV-2 has evolved a mechanism to counteract its action via PLpro-mediated proteasomal degradation.

Metagenomic next-generation sequencing has the potential to support diagnosis of unknown infections as it can identify all potential pathogens without requiring a prior suspected cause. Here, the authors develop and clinically validate a metagenomics-based assay for common and novel respiratory viral pathogens.

Teplizumab is clinically approved for delaying the onset of type 1 diabetes, with the responses affected by EBV serology status. Here the authors pursue immune profiling of EBV⁺ or EBV^- participants before and after teplizumab treatment to find more pronounced immune modulation in treated EBV⁺ individuals to hint a cellular mechanism for this EBV effect.

The analysis of essential genes in pathogens can be used to discover potential antimicrobial targets. Here, the authors use a machine learning model and chemogenomic analyses to generate genome-wide gene essentiality predictions for the fungal pathogen Candida albicans, define the function of three uncharacterized essential genes, and identify the target of a new antifungal compound.

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.

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.

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.

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.