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There is currently no approved vaccine for Lassa fever virus (LASV). Here, Abreu-Mota et al. develop an inactivated, adjuvanted vaccine candidate expressing LASV glycoprotein (GPC) in a rabies virus vector, and show that non-neutralizing LASV GPC-specific antibodies are a major mechanism of protection.

Linking epigenetic marks to clinical outcomes promises insight into the underlying processes. Here, the authors introduce a statistical approach to estimate associations between a phenotype and all epigenetic probes jointly, and to estimate the proportion of variation captured by epigenetic effects.

In a second concluding article, Peter Pockley looks at Australian science and the recent election.

Anxiety is characterized by altered responses under uncertain conditions. Aylward et al. show that these altered responses are due to anxious individuals updating their behaviour in response to negative outcomes more quickly than non-anxious individuals.

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

Derailed differentiation of human-specific progenitors of the developing cerebellar rhombic lip is the cause of group 4 medulloblastoma, the most common childhood brain tumour. 

A class of chimeric synthetic antibiotics that bind to lipopolysaccharide and BamA shows potent activity against multidrug-resistant Gram-negative bacteria, with the potential to address life-threatening infections.

Analyses of multiregional tumour samples from 421 patients with non-small cell lung cancer prospectively enrolled to the TRACERx study reveal determinants of tumour evolution and relationships between intratumour heterogeneity and clinical outcome.

Emerging variants of SARS-CoV-2 raise concerns about vaccine efficiency. Here, the authors present a post-hoc analysis for the ChAdOx1 nCoV-19 (AZD1222) vaccine trial in Brazil and provide efficacy against symptomatic COVID-19 caused by the Zeta (P.2) and other variants.

An integrated transcriptome, genome, methylome and proteome analysis of over 200 lung adenocarcinomas reveals high rates of somatic mutations, 18 statistically significantly mutated genes including RIT1 and MGA, splicing changes, and alterations in MAPK and PI(3)K pathway activity.

The mechanisms that govern the transdifferentiation of lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) are not fully understood. Here, the authors show that EZH2 loss exacerbates the transdifferentiation of ADCs to SCCs as a result of chromatin changes that lead to expression of squamous differentiation genes.

Eukaryotes acquired their prokaryotic genes in two episodes of evolutionary influx corresponding to the origin of mitochondria and plastids, respectively, followed by extensive differential gene loss, uncovering a massive imprint of endosymbiosis in the nuclear genomes of complex cells.

Elevated intraocular pressure (IOP) is a heritable risk factor for primary open angle glaucoma. Using forward mouse genetics, cell biology, pharmacology and human genetic data, the authors identify CACNA2D1 as an IOP risk gene that can be therapeutically targeted by the drug pregabalin in animal models.

The authors demonstrate 3D chemical imaging of organic and inorganic materials near or below one-nanometer resolution using multi-modal electron tomography, by fusing elastic and inelastic scattering signals.

Patient-derived xenografts are important tools for cancer drug development. Here, the authors develop models from 22 non-small cell lung cancer patients. They show genomic differences between models created from different spatial regions of tumours and a bottleneck on model establishment.

A rare constitutional translocation between chromosomes 15 and 21 predisposes to catastrophic chromosomal damage followed by amplification of megabase regions, causing a specific subtype of acute lymphoblastic leukaemia.

Mixed responses to targeted therapy within a patient are a clinical challenge. Here the authors show that TP53 loss-of-function cooperates with whole genome doubling which increases chromosomal instability. This leads to greater cellular diversity and multiple routes of resistance, which in turn promotes mixed responses to treatment.

The sensitivities of a set of bacterial metal-sensing transcriptional regulators explain how a protein, such as the cobalt chelatase CbiK, is metalated with its cognate metal in cells rather than mis-metalated with more tightly binding metals.

Whole-genome sequencing of healthy human epithelial crypts from the small intestines of 39 individuals highlights APOBEC enzymes as a common contributor to the overall mutational burden in this tissue.

Time-resolved serial femtosecond crystallography is used to reveal the structural changes that stabilize the charge-separation steps of electron-transfer reactions in the photosynthetic reaction centre of Blastochloris viridis on a timescale of picoseconds.

Identifying biomarkers associated with risk of severe COVID-19 disease could inform clinical management. Here, the authors identify a long noncoding RNA associated with severe disease using data from three European countries, and validate their finding in data from Canada.

DNA methylation targets CpG island promoters of germline genes to repress their expression in mouse somatic cells. Here the authors show that a transcription factor E2F6 is required to target CpG island DNA methylation and epigenetic silencing to germline genes during early mouse development.

Peter Campbell, Mel Greaves and colleagues use exome and whole-genome sequencing to characterize somatic mutations in childhood acute lymphoblastic leukemias with the ETV6-RUNX1 fusion gene. They find that RAG-mediated deletions are the dominant mutational process.

Common polygenic variation at chromosome 16p and rare recurrent deletions of 16p11.2 influencing autism risk are associated with reduced expression of genes throughout the 16p region, suggesting functional convergence of rare and common variant effects.

Pore-forming toxins act by forming oligomeric pores in lipid membranes. Here the authors report the crystal structure of the lysenin pore, providing insights into the assembly and function of the pore in addition to suggesting that its properties make lysenin potentially well-suited for nanopore sensing applications.

Extensive genetic analysis of over 2,000 individuals from different locations in Britain reveals striking fine-scale patterns of population structure; comparisons with similar genetic data from the European continent reveal the legacy of earlier population migrations and information about the ancestry of current populations in specific geographic regions.

Post-international travel quarantine has been widely implemented to mitigate SARS-CoV-2 transmission, but the impacts of such policies are unclear. Here, the authors used linked genomic and contact tracing data to assess the impacts of a 14-day quarantine on return to England in summer 2020.

Cryo-EM structures of human SERINC5 and its fly orthologue, along with extensive functional analyses, reveal the protein architecture and identify regions important for HIV-1 restriction.

The extent to which COVID-19 vaccination protects against long COVID is not well understood. Here, the authors use electronic health record data from the United States and find that, for people who received their vaccination prior to infection, vaccination was associated with lower incidence of long COVID.

The authors report the mutational landscape of 29 cell types from microdissected biopsies from 19 organs and explore the mechanisms underlying mutation rates in normal tissues.

Whole-genome sequencing of tumours from 560 breast cancer cases provides a comprehensive genome-wide view of recurrent somatic mutations and mutation frequencies across both protein coding and non-coding regions; several mutational signatures in these cancer genomes are associated with BRCA1 or BRCA2 function and defective homologous-recombination-based DNA repair.

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.

XFEL radiation is providing new opportunities for probing biological systems. Here the authors perform nanoscale x-ray imaging of microtubules with helical symmetry, by using imaging sorting and reconstruction techniques.

An online approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups has been developed to help to improve current diagnostic standards.

Vitamin D deficiency is associated with multiple human pathologic conditions. In a genome-wide association study of 79,366 individuals, Jiang et al. replicate four and identify two new genetic loci for serum levels of 25-hydroxyvitamin D and find evidence for a shared genetic basis with autoimmune diseases.

It is unclear whether somatic mutation rates are elevated in Lynch Syndrome (LS), which is the most common cause of hereditary colorectal cancer. Here, the authors use whole-genome sequencing and organoid cultures to show that normal tissues in LS patients are genomically stable, while ancestor cells of neoplastic tissues undergo multiple cycles of clonal evolution.