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Nature Biotechnology asks a selection of researchers about the most exciting frontier in their field and the most needed technologies for advancing knowledge and applications.

Youti yuanshi is a euarthropod species newly described from a fossilized larva from Yunnan Province, China dating approximately to late Atdabanian stage, Cambrian period, and provides insights into the evolution of arthropods.

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 authors analyze rare coding variants in 1990 individuals with congenital kidney anomalies, finding diagnostic variants in 14.1% of cases. They identify two new causal genes, ARID3A and NR6A1, along with 38 candidate genes, providing evidence for shared genetics with other developmental disorders.

The APOE4 allele is a major genetic risk factor for the development of late-onset Alzheimer’s disease (AD). In this manuscript, Butovsky and colleagues suggest that APOE4 impairs the microglial response in AD by inducing TGFβ-mediated checkpoints.

Long-circulating, transfection-competent LNP-mRNA systems are key for effective extrahepatic delivery. Here, authors show that LNPs with high bilayer lipid ratios yield high mRNA encapsulation, prolonged circulation, and enhanced transfection in extrahepatic tissues.

Analysis of EZH2 separation-of-function mutants indicates that part of the RNA-binding surface of EZH2 is necessary for histone modification independently of RNA. A specific RNA-binding-defective mutant shows normal enzymatic activity in vitro and in lineage-committed cells.

In a previous clinical trial, the authors reported that SCFA-yielding biotherapy in adults with type 1 diabetes remodels the gut proteome and metabolome. Here, the show that colonization of the post-therapy microbiome into mice delayed diabetes and increased aryl-hydrocarbon receptor ligand and IgA production in the gut.

BRAF or MEK1/2 inhibitors are cytostatic in melanoma and the surviving cells develop drug resistance. This study shows that the pro-survival pool is biased towards MCL1 in melanoma so that BRAF or MEK1/2 inhibitors are synthetic lethal with the MCL1 inhibitor AZD5991, improving tumour growth inhibition.

Immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS) infers B cell and T cell fractions from whole-genome sequencing data. Applied to the 100,000 Genomes Project datasets, circulating T cell fraction provides sex-dependent and prognostic insights in patients.

Frontotemporal dementia (FTD) is a common early-onset dementia caused by heterozygous mutations in the progranulin gene (GRN). Gerrits et al. demonstrate blood–brain barrier dysfunction and a severely affected neurovasculature in FTD-GRN.

A new study shows that the orphan nuclear receptor liver receptor homolog 1 (LRH-1) wires the postovulatory rise in progesterone production to progesterone-dependent preparation of the endometrium for pregnancy, a process termed decidualization. Lack of Lrh-1 activity in either the ovary or uterus has catastrophic consequences for reproduction in mice (pages 1061–1066).

A metabolic system of engineered biocatalysts using the noncanonical cofactor nicotinamide mononucleotide is established for biomanufacturing in cell-free systems and in Escherichia coli without interference from nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate.

Swanton and colleagues present a clonal expression signature, ORACLE, which, in combination with clinicopathological and molecular risk factors, can predict survival of patients with lung adenocarcinoma, and they prospectively validate its prognostic value.

Imaging dozens of proteins in situ and at large scales increases the complexity of data analysis. Here, the authors develop an end-to-end solution for multiplexed image analysis that facilitates data interpretation for clinically relevant insights.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Retrotransposition events have been linked to some human disorders. Here, Gardner et al. systematically search for mobile genetic elements (ME) in trio whole exome-sequencing datasets and ascertain 9 de novo MEs and further estimate genome-wide germline ME burden and constraint.

COVID-19 can be associated with neurological complications. Here the authors show that markers of brain injury, but not immune markers, are elevated in the blood of patients with COVID-19 both early and months after SARS-CoV-2 infection, particularly in those with brain dysfunction or neurological diagnoses.

Lipid membranes are hard to visualise in tissues with nanoscale precision. The authors report ultrastructural membrane expansion microscopy (umExM), a tool that enables dense membrane labelling for nanoscale imaging of cellular membranes using a standard confocal microscope.

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

A study reports whole-genome sequences for 490,640 participants from the UK Biobank and combines these data with phenotypic data to provide new insights into the relationship between human variation and sequence variation.

A regional oxygenation event 1.6 billion years ago coincided with the appearance of large fossils, but whether the availability of oxygen was the primary driver of the diversification of multicellular organisms remains to be seen.

In this study, Papalazarou et al. screen the solute carrier family and identify candidates involved of serine transport in colorectal cancer cells. They further characterize cytosolic SLC6A14 and mitochondrial SLC25A15 as mediators of adequate serine supply to sustain cancer cell proliferation.

MISO (MultI-modal Spatial Omics) integrates two or more spatial omics modalities, despite differences in data quality and spatial resolution for improved feature extraction and clustering to reveal biologically meaningful tissue organization.

Why do chemists make compounds that could blow up in their faces? Emma Marris finds out... from a safe distance.

Investigation of variation in three cohorts has identified multiple genetic signals associated with the pregnancy-specific liver disorder, intrahepatic cholestasis of pregnancy, giving insight into the disease which can cause preterm birth and stillbirth.

Necroptosis is a regulated form of inflammatory cell death driven by activated MLKL. Here, the authors identify a mutation in the brace region that confers constitutive activation, leading to lethal inflammation in homozygous mutant mice and providing insight into human mutations in this region.

STAG2 is a core subunit of the cohesin complex involved in DNA looping, but its transcriptional targets are largely unknown. Here the authors show STAG2 controls the 3D chromatin structure at the IRF9 locus to restrict IRF9 expression. Loss of STAG2 results in IRF9 activation, which in turn upregulates PD-L1 expression in cancer cells, suggesting a tumor suppressor function in immune evasion.

The origin of the charge density wave in vanadium antimonides has been widely debated. Here, the authors report the cooperation of electron-phonon and phonon-phonon coupling for the formation of the charge density wave in CsV₃Sb₅.

By combining large-scale first-principles GW-BSE calculations and micro-reflection spectroscopy, the nature of the exciton resonances in WSe₂/WS₂ moiré superlattices is identified, highlighting non-trivial exciton states and suggesting new ways of tuning many-body physics.

A global multi-taxon extinction risk assessment of freshwater fauna for The IUCN Red List of Threatened Species finds one-quarter of species to be at high risk of extinction.

Inborn errors of the alternative NF-κB pathway in humans impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases

Protein immunofluorescence imaging and affinity purification–mass spectrometry are combined to create a unified map of human cell architecture across scales, which the authors call the multi-scale integrated cell (MuSIC).

Cas12a is widely used in diagnostic platforms. Here the authors show that Cas12a can be programmed to directly detect RNA substrates, this is due to the 3’-end of the crRNA tolerating both RNA and DNA substrates: they use this to report a method, SAHARA, to detect RNA sequences.

Antivirals are now available for treating COVID-19 but must be used early in the course of infection to be effective. Here, the authors use mathematical modelling to assess the potential public health impacts of antiviral use considering different levels of testing and country sociodemographic characteristics.

Mapping enhancer-target gene pairs with single-cell multimodal data is challenged by the data’s unique characteristics and computational demands. Here, the authors propose scMultiMap, a statistical method with high statistical power and computational efficiency for inferring their associations.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Alcohol use disorder and drinks per week both have been studied genetically and have different correlations with psychiatric diseases. Here the authors integrate multi-omics data to identify unique and shared variants, genes and pathways for alcohol use disorder and drinks per week.

The Programmed death-1 (PD-1) and its ligand PD-L1 are critical checkpoints in the regulation of immune responses. Here the authors implicate PD-L1 signalling at lymphatic endothelium in the regulation of transendothelial migration of T cells.

Different functional variants in ADH1B (and elsewhere) in Europeans and Africans strongly affect risk for alcohol dependence. Dependence only partly genetically correlates with consumption, with strong correlations to other psychiatric disorders.

Carbapenem-resistant Acinetobacter baumannii is an important nosocomial pathogen that can cause outbreaks. In 2019, these authors conducted a genomic surveillance study of A baumannii in an intensive care unit in China, and here they report findings from a follow up study in 2021.

Quiescent sub-populations of cells in tumours are resistant to traditional chemotherapeutics and are responsible for tumour recurrence. Here, Zhang et al. identify a compound that kills quiescent tumour cells in solid tumour tissue by inducing mitochondrial dysfunction.

A longitudinal evolutionary analysis of 126 lung cancer patients with metastatic disease reveals the timing of metastatic divergence, modes of dissemination and the genomic events subject to selection during the metastatic transition.

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.

The authors pooled resources to identify best practices and develop a new standardized protocol for estimating functional connectivity in rats with magnetic resonance imaging.

Jeppesen, Sanchez et al. identify blebbisomes as large membrane-enclosed vesicles containing organelles and secreted by cells. Blebbisomes can both secrete and internalize exosomes and microvesicles.