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Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

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.

Obesity is a global pandemic with limited treatment options. Here, the authors show evidence in mice that the mitochondrial uncoupler BAM15 effectively induces fat loss without affecting food intake or compromising lean body mass.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

Genotype and exome sequencing of 150,000 participants and whole-genome sequencing of 9,950 selected individuals recruited into the Mexico City Prospective Study constitute a valuable, publicly available resource of non-European sequencing data.

Typical quantum error correcting codes assign fixed roles to the underlying physical qubits. Now the performance benefits of alternative, dynamic error correction schemes have been demonstrated on a superconducting quantum processor.

Comparison of multiple genome assemblies from wheat reveals extensive diversity that results from the complex breeding history of wheat and provides a basis for further potential improvements to this important food crop.

The relative importance of imported compared to local transmission of malaria in island populations is difficult to quantify. Here, the authors perform a quasi-experimental study to assess how travel restrictions to Bioko Island, Equatorial Guinea during the COVID-19 pandemic impacted the prevalence of malaria on the island.

Experimental measurements of high-order out-of-time-order correlators on a superconducting quantum processor show that these correlators remain highly sensitive to the quantum many-body dynamics in quantum computers at long timescales.

Complete sequences of chromosomes telomere-to-telomere from chimpanzee, bonobo, gorilla, Bornean orangutan, Sumatran orangutan and siamang provide a comprehensive and valuable resource for future evolutionary comparisons.

A high-bandwidth neuromotor interface offers performant out-of-the-box generalization across people.

Reference assemblies of great ape sex chromosomes show that Y chromosomes are more variable in size and sequence than X chromosomes and provide a resource for studies on human evolution and conservation genetics of non-human apes.

A high-resolution, global atlas of mortality of children under five years of age between 2000 and 2017 highlights subnational geographical inequalities in the distribution, rates and absolute counts of child deaths by age.

The association of telomere length with age and mortality across racially diverse pulmonary fibrosis populations is unknown. Here, the authors show that leukocyte telomere length associates with chronologic age and is predictive of mortality in pulmonary fibrosis across racial groups.

The 3CL protease of SARS-CoV-2 is inhibited by PF-00835231 in vitro. Here, the authors show that the prodrug PF-07304814 has broad spectrum activity, inhibiting SARS-CoV and SARS-CoV-2 in mice and its ADME and safety profile support clinical development.

It is unclear why different antibiotics vary in their ability to shorten treatment of tuberculosis. Here, the authors show that a measure based on ribosomal RNA synthesis in Mycobacterium tuberculosis correlates with treatment shortening in culture, in mice and in human studies.

This Registered Report presents the results of the Long-read RNA-Seq Genome Annotation Assessment Project, which is a community effort for benchmarking long-read methods for transcriptome analyses, including transcript isoform detection, quantification and de novo transcript detection.

Itkin et al. identify a role for Fli-1 in hematopoietic stem cell activation during regenerative hematopoiesis. They show that Fli-1 coordinates hematopoietic stem cells to stimulate niche-derived Notch1 feedback signals for demand-needed hematopoietic cell output.

Wesley et al. describe the developmental trajectories of human foetal liver cell types at single-cell resolution and generate bipotential hepatoblast organoids, which can serve as a new platform to investigate human liver development.

Activation of the non-canonical NF-κB signalling pathway by AZD5582 results in the induction of HIV and SIV RNA expression in the blood and tissues of antiretroviral-therapy-treated humanized mice and rhesus macaques.

Phenotypic variation and diseases are influenced by factors such as genetic variants and gene expression. Here, Barbeira et al. develop S-PrediXcan to compute PrediXcan results using summary data, and investigate the effects of gene expression variation on human phenotypes in 44 GTEx tissues and >100 phenotypes.

Biological determinants for developing post-acute sequelae of SARS-CoV-2 infection are largely unclear. Here, by comparing markers during acute infection in individuals who developed PASC with those who recovered, the authors found that early viral dynamics and immune responses might play a role in PASC pathogenesis.

Morey and colleagues identify a dual function of CoREST in regulating sensitivity and resistance to endocrine therapies in breast cancer. This work also provides a pre-clinical model for study of the conversion of luminal/ER⁺ to basal/ER⁻ breast cancer.

Depletion of CD8⁺ T cells before infection or early antiretroviral therapy initiation elucidates the role of cytotoxic T lymphocytes during formation of the latent simian immunodeficiency virus reservoir.

Insights on the mechanistic differences between artificial metalloenzymes (ArMs) with non-native metal centres and the free cofactor or natural enzymes are scarce. Now, a detailed mechanistic analysis of a cyclopropanation reaction catalysed by such an ArM is provided, revealing intriguing differences to the natural system.

Bhattacharjee and Schaeffer et al. map exclusive breastfeeding (EBF) in 94 low- and middle-income countries (LMICs), finding increased EBF practice and reduced subnational variation across the majority of LMICs from 2000 to 2018. However, only six LMICs will meet WHO’s target of ≥70% EBF by 2030 nationally, and only three will achieve this in all districts.

Although progress in the coverage of routine measles vaccination in children in low- and middle-income countries was made during 2000–2019, many countries remain far from the goal of 80% coverage in all districts by 2019.

A study presents a cross-species proteomic map of synapse development in neocortex and reveals that the human postsynaptic density assembly develops two to three times slower than that in macaques and mice.

Grapevine is one of a few ancestrally dioecious crops that are reverted to hermaphroditism during domestication. Here, the authors identify candidate genes related to male- and female-sterility in grapes and describe the genetic process that led to hermaphroditism during domestication.

Polymerase theta is a widely conserved DNA polymerase that mediates Theta Mediated End Joining. Here authors present a synthetic lethal CRISPR screen to identify DDR gene mutations that induce cellular addiction to Pol theta.

Analyses of the relationships between temperature, moisture and seven key plant functional traits across the tundra and over time show that community height increased with warming across all sites, whereas other traits lagged behind predicted rates of change.

Suppressor tRNAs adapted to the amino acid that they carry enable readthrough of premature termination codons introduced by nonsense mutations and show potential for the treatment of genetic diseases such as cystic fibrosis.

Germline mutations in the Elongator complex gene ELP1 predispose individuals to the development of childhood medulloblastoma.

The GREGoR consortium provides foundational resources and substrates for the future of rare disease genomics.

A phase 1/2a study shows that human neural progenitor cells modified to release the growth factor GDNF are safely transplanted into the spinal cord of patients with ALS, with cell survival and GDNF production for over 3 years.

Two below-threshold surface code memories on superconducting processors markedly reduce logical error rates, achieving high efficiency and real-time decoding, indicating potential for practical large-scale fault-tolerant quantum algorithms.

Rps genes are used to manage the major soybean pathogen Phytophthora sojae, which causes Phytophthora stem and root rot (PRR). Here, the authors show that widely used Rps genes are no longer effective for managing PRR in the United States, Canada and Argentina.

The apparent respiratory quotient for bacterioplankton remineralization of dissolved organic matter (DOM) is influenced by DOM composition and the metabolic potential of bacteria, accounting for variability in large-scale CO2 production estimates.

The identification of antibodies targeting a conserved site of vulnerability in the Plasmodium falciparum circumsporozoite protein reveals opportunities for passive prevention of malaria in vulnerable individuals and provides insights for rational vaccine design.

Evidence showing that carbonates can directly supply CO₂ for autotrophy is lacking. Here, using stable isotope analyses and NanoSIMS imaging, the authors show that a model euendolith, Mastigocoleus testarum strain BC008, derives the majority of its biomass carbon from the mineral carbonates it excavates.

Stabilization of DNA quadruplex structures (G4) is lethal for cells with a compromised DNA repair pathway. Here, the authors show that CX-5461, a small molecule in clinical trials as RNA polymerase inhibitor, has G4-stablization properties and can be repurposed to target DNA repair-defective cancers cells.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

RIG-I is a critical receptor in the induction of innate immune responses, but mutations in RIG-I can be associated with hyperactive signalling and autoimmune disease. Here Zheng et al. apply HDX-MS approaches to reveal dysregulated checkpoints that result in recognition of self-derived RNA during RIG-I mediated autoimmunity.

A randomized trial in patients hospitalized with COVID-19 showed no benefit and potentially increased harm associated with the use of convalescent plasma, with subgroup analyses suggesting that the antibody profile in donor plasma is critical in determining clinical outcomes.

Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.

The National Cancer Institute (NCI) Genomic Data Commons (GDC) contains more than 2.9 petabytes of genomic and associated clinical data from more than 60 NCI-funded and other contributed cancer genomics research projects. The GDC consists of five applications over a common data model and a common application programming interface.