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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.

Computationally designed TRI2-2 miniprotein inhibitor broadly neutralizes multiple SARS-CoV-2 Omicron variants and confers post-exposure protection in mice against BQ.1.1, XBB.1.5, and BA.2.86 challenge when administered intranasally.

The spike protein of the Omicron variant of SARS-CoV-2 has a higher affinity for ACE2 than Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic and vaccine-elicited neutralizing antibodies.

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

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 role of successional state in determining ecosystem sensitivity to climate change is largely unknown. Here, the authors subject seven European shrublands to moderate warming and drought conditions over 14 years and show that responsiveness is associated with the dynamic state of the ecosystem.

Pressure is mounting to relax the regulations on importation of chimpanzees for research. Such a policy is unnecessary and would deepen the plight of an already endangered species.

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.

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.

Synovial sarcoma (SS) is a difficult-to-treat cancer, driven by the fusion oncoprotein SS18::SSX. SS18::SSX alters the BAF (mammalian SWI/SNF) chromatin remodelling complex to create an oncogenic transcriptome. Here, the authors identify SS18::SSX-driven SMARCE1 SUMOylation as a therapeutic vulnerability in SS and show that SUMOylation inhibition stabilizes the cBAF complex, inducing cell death and sensitization of SS to chemotherapy.

This study demonstrated that different types of HC-Pros from potyviruses exhibit varying capacities to inhibit HEN1. This results in distinct levels of autophagic AGO1 degradation, which in turn leads to differences in RNA silencing suppression efficiency.

BRCA1 loss can result in collapse of replication forks into DNA double strand breaks that can contribute to malignant transformation. Here, the authors find that BRCA1 promotes the expression of RRM2 protecting glioblastoma cells from replication stress, DNA damage and apoptosis.

The authors identify a Cys→Ser transformation (C19S) in insulin leading to neoepitope presentation and CD4⁺ T cell autoreactivity in type 1 diabetes. Inflammation and oxidative stress enhanced C19S transformation in β cells and antigen-presenting cells, resulting in C19S-specific CD4⁺ T cells with an activated memory phenotype linked to disease progression.

In this study, Aggarwal and colleagues perform prospective sequencing of SARS-CoV-2 isolates derived from asymptomatic student screening and symptomatic testing of students and staff at the University of Cambridge. They identify important factors that contributed to within university transmission and onward spread into the wider community.

Preclinical models that faithfully recapitulate interactions between the human immune system and tumours are necessary to evaluate human-specific immunotherapies in vivo; however, their number is currently limited. The authors of this Review discuss the currently available humanized mouse models, which are immunodeficient mice co-engrafted with human tumours and immune components, with a focus on their applicability in translational research.

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.

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.

Isolates of authentic SARS-CoV-2 variants BA.1 and BA.2 exhibit similar infectivity and pathogenicity and show susceptibility to neutralizing therapeutic antibodies and antiviral compounds in mouse and hamster models.

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.

Here the authors develop a ferritin-based protein nanoparticle vaccine candidate for SARS-CoV-2, and show induction of neutralizing antibodies to variants of concern, including Omicron BQ.1, in non-human primates after initial immunization and a booster dose.

Together with an accompanying paper presenting a transcriptomic atlas of the mouse lemur, interrogation of the atlas provides a rich body of data to support the use of the organism as a model for primate biology and health.

Jane Qiu investigates the thriving business of selling stem cell transplants as cure-alls for debilitating diseases.

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.

There are over 40 different simian immunodeficiency viruses (SIVs) with which African primates are naturally infected; two of these have crossed the species barrier to generate human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2). Although SIVs do not generally cause AIDS in primates, AIDS-like disease is now shown to occur in chimpanzee populations in the wild who are naturally infected with SIVcpz, a close relative of HIV-1.

A study of SARS-CoV-2 variants examining their transmission, infectivity, and potential resistance to therapies provides insights into the biology of the Delta variant and its role in the global pandemic.

Wildfires are becoming increasingly frequent in several regions around the world due to climate change, posing serious health risks, especially for respiratory diseases. This study examines the respiratory health risk and burden of wildfire-specific PM_2.5 pollution across eight countries and territories.

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.

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.

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.

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.

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.

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.

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.