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There are no vaccines or antivirals available against enterovirus D68. Here, the authors report Jun6504 as a 2C inhibitor and show that it provides broad-spectrum antiviral activity against EV-D68, EV-A71, and CVB3 and potent antiviral efficacy in a neonatal neurological mouse model of EV-D68 infection.

This study identifies E167, Y268, and Q269 as drug-resistant hotspots for SARS-CoV papain-like protease inhibitors that bind to the BL2 loop and groove region, which are valuable in informing the design of the next-generation PLpro inhibitors.

Generations of microbiologists have relied on traditional genetic screening techniques to isolate mutants. Nowadays, advances in high-throughput technologies mean that fluorescent assays can be exploited for the rapid isolation of mutants with complex phenotypes. These single-cell techniques, which include flow cytometry and microfluidic applications, and their uses in microbiology, are discussed in this Review.

Intense solar radiation on desiccated desert soils can cause a short circuit in biogeochemical cycles leading to the release of CO₂and nitrogen oxides. Here, the authors show that this can be linked to the production of soil superoxide radicals, which then produce peroxides and hydroxyl radicals.

Monoclonal antibody (mAb) therapy is now commonplace in the clinic, yet such reagents can elicit unwanted side effects due to interactions with Fcγ receptors. Georgiou and colleagues have engineered mAbs that lack such FcγR interactions but retain the ability to activate complement and show that these modified mAbs have efficacious effector function.

Numerous aerobic bacteria depend on glutathione but are lacking the first enzyme in its biosynthetic pathway. An evolutionary experiment identifies a likely natural route to compensate for this loss through mutations in two enzymes in proline biosynthesis.

Georgiou and colleagues discuss rapidly evolving methods for high-throughput sequencing of the antibody repertoire, and how the resulting data may be applied to answer basic and translational research questions.

Lee et al. report an engineered IgG1 Fc ___domain that behaves like an hFcRn binding pH toggle switch. The authors show that this new half-life extension Fc ___domain confers improved pharmacokinetics in new humanized knock-in mouse strains that recapitulate the key processes for antibody persistence in circulation.

Human immunodeficiency virus type 1 (HIV-1)-neutralizing responses can persist for several years, even at low antigen levels, suggesting that an HIV-1 vaccine may be able to elicit a durable antibody response.

In this work, the authors show that two parallel and distinct evolutionary pathways can lead to genetically diverse enzyme species that harbour similar catalytic activities against the desired substrate, modulated by distinct conformational dynamics during catalysis.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

A survey of T cell repertoire evolution in the tumors, healthy tissue and blood of patients with early-stage untreated lung cancer offers an opportunity to monitor and identify neoantigen-specific T cells for personalized immunotherapy.

Dimethyl fumarate (DMF) is an anti-inflammatory drug proposed as a treatment for COVID19. Here the results are reported from a randomised trial testing DMF treatment in 713 patients hospitalised with COVID-19. DMF was not associated with any improvement in day 5 outcomes.

Immunogenicity concerns preclude the use of bacterial kynureninases for cancer immunotherapy, while the human variant lacks the desired therapeutic effect. A human kynureninase enzyme has now been evolved to reach the activity and substrate specificity of its bacterial counterpart.

Isolation of antigen-specific antibodies or antibody fragments, whether through B-cell immortalization or recombinant libraries, generally requires laborious screening. Reddy et al. circumvent this step using high-throughput sequencing of plasma cells and bioinformatic analysis of the variable-gene repertoire.

Georgiou and colleagues describe a single-cell, emulsion-based approach for the high-throughput determination of the paired antibody variable heavy and light chain (VH-VL) repertoire encoded by the more than 2 × 10⁶ B cells in human peripheral blood samples.

Fire impacts soil organic carbon stocks, in addition to aboveground biomass, yet changes are not well constrained. This study shows that more soil carbon is lost from drier ecosystems than humid ones and that the carbon sink is increasing in savannah–grassland regions with declining burned area.

Mutations in the type I ryanodine receptor (RYR1), a calcium channel, leads to stimulus-induced pathological muscle contractions, including malignant hyperthermia. Currently there are no pharmacological agents to protect against this condition, but Susan Hamilton and her colleagues have now identified AICAR as one possible candidate compound. To date, AICAR has been thought to be an AMPK activator, but her group shows that in a mouse model of malignant hyperthermia it does not target this kinase, but rather RYR1, to prevent improper calcium leakage and pathology.

A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

Longevity of antibody responses has been attributed to persistence of plasma cells in mice. Here the authors provide human data in support of this model by immunoglobulin sequencing bone marrow sections from two human donors over 6.5 years to show temporal stability of plasma cell clonotypes, but not other B cells.

Crystal structures of HIV-1 Env V1V2 in complex with human broadly neutralizing antibodies and ontogeny analyses allow the engineering of Env trimers that are recognized by ancestor and intermediate antibody forms.

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.

Tryptophan depletion, which occurs in tumours, results in in-frame translation across tryptophan-encoding codons by phenylalanine substitution.

The progression of antibody-mediated immunity can now be monitored at high-throughput on a single-cell level.

Knowledge on how antibody responses have evolved is critical for the induction of protective immunity. Here the authors analyse, using high-throughput sequencing of both exon and intron regions, the mutation and lineage development of an HIV-neutralizing antibody to find an unexpected early emergence of broadly neutralizing species.

Interferon-γ induces ferroptotic cell death in tumours by suppressing cystine uptake and promoting lipid peroxidation.

Mutations in the RyR1 channel cause core myopathies. Here the authors show that ER stress and the unfolded protein response underlie the pathology caused by a common RyR1 channel mutation, and show that treatment with a chemical chaperone restores muscle function in mice.

Wu et al. utilize multiparametric analysis of early-stage human NSCLC to characterize a population of Vδ1 T cells displaying a resident memory and effector memory phenotype, which were associated with ongoing remission.

RNA sequencing data and tumour pathology observations of non-small-cell lung cancers indicate that the immune cell microenvironment exerts strong evolutionary selection pressures that shape the immune-evasion capacity of tumours.

Analysis of whole-genome doubling (WGD) by using cancer sequencing data combined with simulations of tumor evolution suggests that there is negative selection against homozygous loss of essential genes before WGD but not after.

Circulating tumour DNA profiling in early-stage non-small-cell lung cancer can be used to track single-nucleotide variants in plasma to predict lung cancer relapse and identify tumour subclones involved in the metastatic process.

Between around 5,000 to 2,000 years ago, a drying climate in the vast peatlands of the Congo Basin triggered peat decomposition and carbon release to the atmosphere, implying that this region may be vulnerable to future climate change.

By reducing the availability of extracellular L-cyst(e)ine, an engineered enzyme inhibits glutathione production and cripples antioxidant defenses of tumors in a variety of mouse models.

Cathepsin S is responsible for cleaving the invariant chain Ii for the presentation of peptides by major histocompatibility complex class II on DCs. Diamond and colleagues show that the transcription factor Blimp-1 negatively regulates expression of cathepsin S and influences selection of the T_FH cell repertoire and autoantibody-producing B cells.