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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.

Analysis of data from pre-implantation genetic testing sheds light on the genetic basis of meiotic-origin aneuploidy, the leading cause of human pregnancy loss, identifying common genetic variants associated with maternal meiotic errors.

Structurally resolving glycans remains a challenge. Here, the authors analyse influenza H3 hemagglutinin glycan evolution to show that over five decades of glycan incorporation highly impact structural stability and epitope accessibility, particularly in the head domain, providing key insights for vaccine design.

The robust detection of single nucleotide variants (SNVs) remains a key challenge for rapid and multiplexed diagnostics. Now it is shown that FARSIGHT, a computationally designed aptamer-based RNA switch, achieves rapid, enzyme-free genotyping via domino-like coupled strand-displacement reactions. These systems provide attomolar sensitivity when coupled with isothermal amplification, multiplexed SNV discrimination and lateral flow readout.

TIRTL-seq is a high-throughput method for paired T cell receptor sequencing at the cohort scale.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

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.

PepMLM designs peptide binders against diverse targets using masked language modeling.

The authors find that TDP-43 loss of function—the pathology defining the neurodegenerative conditions ALS and FTD—induces novel mRNA polyadenylation events, which have different effects, including an increase in RNA stability, leading to higher protein levels.

Main-group analogues to fullerene-C₆₀ have been predicted theoretically many times. Now, B₄₀⁻ has been observed using photoelectron spectroscopy and, with its neutral analogue, B40, confirmed computationally. In contrast to fullerene-C₆₀, the all-boron fullerene (or borospherene) features triangles, hexagons and heptagons, bonded uniformly by delocalized σ and π bonds over the cage surface.

Self-assembled multidomain supramolecular peptide hydrogels that engage in dynamic covalent bonding with small-molecule drugs and biologics are shown to offer sustained release, extend the activity, and maintain safe and potent drug levels in vivo.

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.

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.

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 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.

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.

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.

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 authors describe a mechanism for the clearance of macromolecules from cerebrospinal fluid in which macromolecules traverse from periarterial to perivenous spaces, at sites where intersecting leptomeningeal perivascular (arteriovenous) spaces overlap.

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.

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.

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.

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.

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.

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.

Stable anti-ambipolar organic materials are limited, thus preventing the design of integrated, tunable, and multifunctional neuromorphic systems. Here, the authors report a small form factor neuromorphic circuit based on organic anti-ambipolar materials, mimicking the pre-processing functions of the retina.

Circulating cell-free DNA (cfDNA) assays for monitoring individuals with cancer typically use tumor-specific mutations that may not be detected in many patients. Here, the authors develop a tumor-independent and mutation-independent approach (DELFI-TF) to estimate tumor burden in cfDNA for treatment response monitoring and clinical outcome prediction.

Hydronium ions bordering cancer cells are highly concentrated into a small extracellular region, and in tumour tissue such severely polarized acidity correlates with the expression of monocarboxylate transporters and with the exclusion of cytotoxic T cells.

Knee osteoarthritis has a sex-specific phenotype with post-menopausal persons experiencing the highest incidence. Here the authors investigate the underlying mechanisms in a mouse model of menopause and find that the loss of 17β-estradiol and progesterone enhanced susceptibility to senescence, extracellular matrix disassembly and cartilage degradation.

Many montane birds seasonally migrate between elevations. This study shows two bird species exhibit phenotypic plasticity in response to this altitude shift: the small-scale elevational migrant shows greater temperature-driven plasticity, while the large-scale migrant displays stronger hypoxia-driven plasticity.

Hundreds of RNAs and proteins are imaged in fixed tissue at subcellular resolution.

The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

Liver macrophages are a major obstacle to extrahepatic drug delivery. This study identifies the receptor–ligand interactions that they use to capture circulating nanoparticles and leverages this understanding to engineer nanoparticles that escape macrophage uptake.

When monkeys are infected with a virus similar to HIV, treated with antiretroviral therapy (ART), and are administered a ‘combo therapy’ made of antibodies against molecules that inhibit immune responses, they control viral rebound when ART is discontinued for more than 6 months

The stability of perovskite tandem solar cells is an issue. Li et al. show that diamines improve the compositional homogeneity of a low-bandgap perovskite surface and form a low-dimensional barrier that passivates defects, leading to an operational stability of over 1,000 h.

Narrow, long graphene nanoribbons with atomically smooth and defect-free edges can be produced by squashing carbon nanotubes, and can be used to fabricate a sub-3-nm-wide channel field-effect transistor with a mobility of 2,443 cm² V⁻¹ s⁻¹.

fMRI reveals similar topography, selectivity and inter-connectedness of language brain areas across 45 languages. These properties may allow the language system to handle the shared features of languages, shaped by biological and cultural evolution.

Dense calcium imaging combined with co-registered high-resolution electron microscopy reconstruction of the brain of the same mouse provide a functional connectomics map of tens of thousands of neurons of a region of the primary cortex and higher visual areas.

Tumour endothelial cell macropinocytosis is the dominant mechanism for nanoparticle entry into the tumour. Enhanced nanoparticle tumour accumulation may be due to upregulated macropinocytosis membrane ruffling compared with most healthy tissues.

This study proposes a computational panel reduction method for CyCIF, leveraging 9 markers to impute information from 25, enhancing speed, content, and reducing costs.