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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.

DiNardo et al. perform a phase 1b/2 clinical trial of telaglenastat (CB-839) in combination with azacytidine in persons with advanced myelodysplastic syndromes and report on the treatment safety and efficacy, including a definition of clinical responders.

High-depth sequencing of non-cancerous tissue from patients with metastatic cancer reveals single-base mutational signatures of alcohol, smoking and cancer treatments, and reveals how exogenous factors, including cancer therapies, affect somatic cell evolution.

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 consensus cell type atlas for the fly brain provides both an intellectual framework and open-source toolchains for brain-scale comparative connectomics.

Genome-wide analyses in over one million self-reported cases and controls identify genetic variants associated with stuttering and find genetic correlations with autism, depression and impaired musical rhythm, supporting a potential neurological basis for stuttering.

An integrative genomic analysis of several hundred endometrial carcinomas shows that a minority of tumour samples carry copy number alterations or TP53 mutations and many contain key cancer-related gene mutations, such as those involved in canonical pathways and chromatin remodelling; a reclassification of endometrial tumours into four distinct types is proposed, which may have an effect on patient treatment regimes.

Coordinating protein translation with energy supply is a significant challenge faced by cells. Here, the authors found that the protein quality control network may provide a link between the two.

FlyWire presents a neuronal wiring diagram of the whole fly brain with annotations for cell types, classes, nerves, hemilineages and predicted neurotransmitters, with data products and an open ecosystem to facilitate exploration and browsing.

Multi-ancestry genome-wide association analyses identify new risk loci for Parkinson’s disease, and fine-mapping and co-localization analyses implicate candidate genes whose expression is associated with disease susceptibility.

A multi-frequency observing campaign of the γ-ray burst GRB 190114C reveals a broadband double-peaked spectral energy distribution, and the teraelectronvolt emission could be attributed to inverse Compton scattering.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

An international consortium reports the genomic sequence for ten Drosophila species, and compares them to two other previously published Drosophila species. These data are invaluable for drawing evolutionary conclusions across an entire phylogeny of species at once.

Statin therapy is associated with numerous cellular effects. Here, the authors show that statin treatment increases post-translational modifications on fatty acid synthase in the active site, revealing communication between the cholesterol and lipid biosynthetic pathways.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

The genome of the grey short-tailed opossum Monodelphis domestica has been sequenced and analyzed, giving a first peek at a marsupial's genetic code. Of particular interest are the genetics of the immune system, which has been studied as a model for humans, and of the X chromosome for historical reasons.

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.

Assessing the accuracy of evapotranspiration (ET) data is crucial for managing the water used by crops and natural vegetation. This study presents a comprehensive evaluation of the accuracy of a remotely sensed ET model ensemble from the OpenET system using in situ ET measurements collected across the contiguous United States.

Cancer and its associated treatment cause debilitating symptom clusters including sickness, nausea, fatigue, pain, distractibility and poor memory. The authors of this Review describe what is known about the mechanisms of the behavioural comorbidities experienced by cancer patients, discuss how cancer-related symptoms develop, and what can be done at the clinical and preclinical levels to better understand their mechanisms and identify appropriate treatments.

The assembly of the genome of the koala provides insights into its adaptive biology and identifies gene expansions that contribute to its ability to detoxify eucalyptus-derived compounds and perceive plant secondary metabolites.

Fourteen cases of new-variant Creutzfeldt–Jakob disease have so far been confirmed in the United Kingdom. Are they the start of an epidemic? If so, how informative will cases in the next few years be in predicting its course?

Aerial and underwater survey data combined with satellite-derived measurements of sea surface temperature over the past two decades show that multiple mass-bleaching events have expanded to encompass virtually all of the Great Barrier Reef.

Ionizing radiation may induce irreparable DNA damage leading to cancer. Here, the authors identify a specific signature of mutations arising in patients exposed to ionizing radiation and suggest that radiation-induced tumorigenesis is associated with higher rates of genome-wide deletions and balanced inversions.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

The measurement of the total cross-section of proton–proton collisions is of fundamental importance for particle physics. Here, the first measurement of the inelastic cross-section is presented for proton–proton collisions at an energy of 7 teraelectronvolts using the ATLAS detector at the Large Hadron Collider.

Hepatocellular carcinoma (HCC) is the fifth most commonly occurring cancer and the third most common cause of cancer-related deaths, and the incidence of this cancer is increasing. A substantial portion of HCCs are thought to arise from hepatic stem cells. In this Review, Lopa Mishra and colleagues describe TGF-β signalling in liver stem cell niches, and examine the roles of this cytokine including those in tumour progression and suppression. Important translational studies that are needed to develop novel therapies are discussed.

Sarat Chandarlapaty and colleagues report the identification of mutations in the ESR1 gene affecting the ligand-binding domain of the encoded estrogen receptor in 20% of metastatic hormone-resistant breast cancers. They determine that the mutant receptor has a hormone-independent active state that likely promotes resistance to estrogen-depriving therapies.

Frank Close enjoys a journalistic account of the sociology and politics of the search for the elusive particle named after physicist Peter Higgs, but cautions that the idea has deeper roots than its name implies.

In September 2012, over 100 experts in cancer research in Africa met in London to discuss the challenges in carrying out high-quality research in this continent. This Review summarizes the discussions and recommendations of this meeting and many examples of successful programmes that have enhanced the development of research in Africa. It also discusses the next steps required to create programmes that will enable evidenced-based cancer control approaches.

Networks of interacting DNA oligomers have various applications in molecular biology, chemistry and materials science, however, kinetic dispersions during DNA hybridization can be problematic for some applications. Here, the authors reveal that limiting unnecessary duplexes using in-silico optimization can reduce in-vitro kinetic dispersions by as much as 96%.

In order to limit warming and the most severe consequences of climate change, net global carbon emissions must reach zero by 2050. Many ecosystems contain carbon that would be irrecoverable on this timescale if lost and must be protected to meet climate goals.

Reanalysis and simulated power analyses for the cross-cultural multi-site study, Many Labs 2, demonstrated low power for detecting cross-cultural heterogeneity.

Nguyen and Thalmann review the benefits and disadvantages of the use of neoadjuvant chemotherapy in patients with bladder cancer, highlighting how clinical and molecular data can aid in personalizing treatment decisions, and discuss possible future application of targeted therapies and immune checkpoint inhibitors in this setting.

Metastasis accounts for the vast majority of cancer deaths. The potential of using nanoparticles to diagnose and to treat metastatic cancer is highlighted in this Review.

This Perspective discusses how high-energy-density physics could tap the potential of AI-inspired algorithms for extracting relevant information and how data-driven automatic control routines may be used for optimizing high-repetition-rate experiments.

A community of researchers report the lessons learned from applying 44 algorithms to predict drug sensitivity in cancer cell lines using genomic, epigenetic and proteomic datasets

Biochemical recurrence after radical prostatectomy or radiation therapy for prostate cancer is increasingly common. The existence of multiple definitions complicates detection of biochemical recurrence and determination of its clinical significance. Here, Ward and Moul assess the relative merits of various definitions, and treatment options including salvage prostatectomy, radiation therapy and cryotherapy, and hormonal treatments.

Pulmonary embolism (PE) is a frequently occurring, acute, and potentially fatal condition. Numerous risk factors for PE have been identified. The diagnostic work-up for PE should comprise safe, efficient and noninvasive methods. In this Review, Renée Douma and colleagues discuss the epidemiology of PE, its risk factors and clinical presentation, together with the latest advances in the diagnostic approach to this condition.

Laparoscopy is important in the treatment of children undergoing renal surgery and for the management of nonpalpable testes. Despite this, laparoscopy is still underutilized in the treatment of urologic disorders in children, compared to adult patients. This Review discusses the most common urologic indications for laparoscopy in pediatric patients and highlights problems that are specific to this patient group.