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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.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

The high-plasticity cell state (HPCS) is a critical hub that enables reciprocal transitions between cancer cell states, and targeting the HPCS may suppress cancer progression and eradicate treatment resistance.

Climate models cannot match long-term observed changes in the tropical Pacific zonal sea surface temperature gradient, implying that model responses to increasing radiative forcing from atmospheric greenhouse gases are diverging from the real world.

A generative artificial intelligence-powered method enables de novo design of highly active enzymes based on information about the geometry of residues in the active site, without requiring protein backbone or sequence information.

Tumour evolution and heterogeneity of recurrent meningioma tumours remains to be explored. Here, the authors perform single nuclei sequencing of matched primary and recurrent meningiomas and reveal diverse cellular compositions and hierarchies.

Therapeutic options for patients with renal medullary carcinoma (RMC) are limited. Here the authors report the results of a phase II clinical trial of anti-PD1 nivolumab plus anti-CTLA4 ipilimumab in RMC, associating the activation of a myeloid mimicry program in tumor cells to the rapid disease progression and hyper-progression observed in treated patients.

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.

A unified realization of the volt, ohm and ampere can be achieved by integrating a quantum anomalous Hall resistor and a programmable Josephson voltage standard in a single cryostat.

Seo et al. present an approach to regulate the formation and optoelectronic quality of the SnO₂ electrodes, improving electroluminescence and efficiency in perovskite solar cells.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Mutations cause impairment of function in the chaperone Hsp60. Here, the authors investigate their impact with MD simulations from the monomer to the 28-mer complex, and show the pervasive effects of mutations on functional dynamics across multiple scales.

Bacterial enzymes synthesize androgens that could promote cancer cell progression interfering with the efficacy of steroid-targeted prostate cancer therapies.

Mammary gland resident macrophages are known to be crucial components of the mammary stem cell niche. Here, the authors show that CXCR4⁺ macrophages form a niche that regulates the tumor-initiating activity of breast cancer cells and induces early immune evasion through the recruitment of regulatory T cells.

Polo-like kinase 3 (Plk3) has a tumor suppressive role through the induction of apoptosis, however, the mechanism underlying its activation is unclear. Here, in pancreatic cancer, the authors show that activation of Plk3 is dependent on its cleavage into p41Plk3, by the metalloendopeptidase nardilysin.

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.

Type 1 polyketides are a major class of natural products with diverse bioactivities but are mostly identified via bioactivity-guided purification which is limited to relatively abundant compounds. Here, the authors present Seq2PKS, a machine learning algorithm that predicts the chemical structures derived from Type 1 polyketide synthases and use it to discover biosynthetic gene clusters for monazomycin, oasomycin A, and 2-aminobenzamideactiphenol.

Using RFdiffusion, a general method for targeting intrinsically disordered proteins and regions for protein design has been developed.

The success of HER2-targeted cancer therapy is limited by treatment resistance. Here, the authors engineer an anti-HER2 biparatopic antibody with multiple mechanisms of action including induction of HER2 clustering to trigger complement dependent cytotoxicity, signal inhibition, antibody dependent cellular cytotoxicity and phagocytosis.

Epichaperomics allow the study of protein-protein interactions and their alterations, but probes have been limited to capturing HSP90 epichaperomes. Here, the authors introduce and validate a toolset of HSP70 epichaperome ligands, and use them in epichaperomics to identify a mechanism with which cancer cells can enhance the fitness of mitotic protein networks.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

A remora-inspired mechanical underwater adhesive device adheres securely to a range of soft substrates and maintains performance under extreme pH and moisture conditions, with potential applications in biosensing and drug delivery.

Woermann and colleagues describe a deaminase-independent function for APOBEC3A in initiating chromosomal instability and STING-dependent metastasis in human and mouse pancreatic cancer.

Exome-sequencing analyses of a large cohort of patients with type 2 diabetes and control individuals without diabetes from five ancestries are used to identify gene-level associations of rare variants that are associated with type 2 diabetes.

Here, the authors show that the soybean GmSNAP02 gene confers a unique mode of resistance to the soybean cyst nematode Heterodera glycines through loss-of-function mutations that implicate GmSNAP02 as a nematode virulence target.

Gastric cancer has two distinct morphologic subtypes, intestinal and diffuse, that differ in genetic composition and clinical manifestation. Here, the authors carry out whole-genome sequencing of diffuse and intestinal gastric cancer samples and characterize the mutational landscape of these different subtypes.

A new inhibitor targeting the mitochondrial complex I shows antitumor activity in preclinical models of acute myeloid leukemia and glioblastoma relying on oxidative phosphorylation.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

Autism is ~4 times more common in males. Jung et al. reveal male-preponderant abnormal behaviors in mice lacking CHD8, a chromatin remodeler, accompanying sexually dimorphic changes in neuronal firing, synaptic transmission, and gene expression.

A dataset of coding variation, derived from exome sequencing of nearly one million individuals from a range of ancestries, provides insight into rare variants and could accelerate the discovery of disease-associated genes and advance precision medicine efforts.

Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

Genome-wide association studies (GWAS) have improved our understanding of the genetic basis of lung adenocarcinoma but known susceptibility variants explain only a small fraction of the familial risk. Here, the authors perform a two-stage GWAS and report 12 novel genetic loci associated with lung adenocarcinoma in East Asians.

Previous studies identified an association between the 2q35 locus and breast cancer. Here, the authors show that a SNP at 2q35, rs4442975, is associated with oestrogen receptor positive disease and suggest that this effect is mediated through the downregulation of a known breast cancer gene, IGFBP5.

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

The molecular determinants of differential responses of different cancer cells to methionine restriction are poorly understood. Here the authors show that hepatocyte nuclear factor 4α regulates sulfur amino acid metabolism and dictates the sensitivity of liver cancer to this dietary manipulation.

An exome-wide association study of six smoking phenotypes in up to 749,459 individuals identifies associations of rare coding variants in CHRNB2 that may reduce the likelihood of smoking.

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.

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 genome-wide association study meta-analysis combined with multiomics data of osteoarthritis identifies 700 effector genes as well as biological processes with a convergent involvement of multiple effector genes; 10% of these genes express the target of approved drugs.

Kyle Gaulton, Mark McCarthy, Andrew Morris and colleagues report fine mapping and genomic annotation of 39 established type 2 diabetes susceptibility loci. They find that the set of potential causal variants is enriched for overlap with FOXA2 binding sites in human islet and liver cells, and they show that a likely causal variant near MTNR1B increases FOXA2-bound enhancer activity, providing a molecular mechanism to explain the effect of this locus on disease risk.

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.

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.

Gut microbiota composition is altered in patients with alcohol use disorder, and fecal microbiota transplant reduced alcohol craving in patients with alcohol use disorder and liver cirrhosis in a phase 1 clinical trial. Here the authors used stool samples collected in the trial to report that this phenotype is transmissible via microbial transfer to germ free mice, as assessed by reduced ethanol acceptance, intake and preference.

First-in-human trial of a self-assembling, ferritin nanoparticle-based influenza vaccine shows evidence that this new platform can elicit neutralizing and cross-reactive antibodies and has potential for further vaccine development.

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.