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The mechanism of action of daptomycin, a lipopeptidic antibiotic, is unclear. Here, the authors show that Ca²⁺-daptomycin simultaneously interacts with lipid-coupled precursors of the bacterial cell envelope and with the anionic phospholipid phosphatidylglycerol, forming a tripartite complex.

Here, combining diagnostic imaging modalities and in vivo assays, Windfelder and colleagues established tobacco hornworm larvae Manduca sexta as an alternative high-throughput platform to study the innate immunity of the gut and host-pathogen interactions. Using the platform, the authors identify mediators of gut inflammation, differentiate pathogens from gut mutualist bacteria, and demonstrate pharmacological interventions.

The authors studied the function of a PIN gene in a filamentous charophyte green alga (Klebsormidium flaccidum). They found that the plasma membrane auxin efflux function is an early trait that emerged before divergence between algae and land plants.

Molecular engineering allows stoichiometric and co-localized expression of two optogenetic actuators, spaced by a fluorescent protein and an additional transmembrane helix in a single protein fusion. The method provides modular optogenetic tools for bidirectional membrane potential control or synergistic effects on neuronal activity.

Increases in transcriptional elongation speed with age affect organismal lifespan and ageing-related changes could be reversed with lifespan-extending interventions.

From 1980 to 2018, the levels of total and non-high-density lipoprotein cholesterol increased in low- and middle-income countries, especially in east and southeast Asia, and decreased in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe.

Pulmonary carcinoids account for about 2% of pulmonary neoplasms. Here, the authors carry out gene copy number analysis, genome/exome, and transcriptome sequencing of pulmonary carcinoids and identify frequent mutations in chromatin-remodelling genes that can drive tumorigenesis in these tumours.

The large virus family,Paramyxoviridae, includes several human and livestock viruses. This study, testing 119 bat and rodent species distributed globally, identifies novel putative paramyxovirus species, providing data with potential uses in predictions of the emergence of novel paramyxoviruses in humans and livestock.

Hair cells of the inner ear have stereocilia that protrude from their apical surface. Sound-induced stereocilial motion is thought to be coupled to mechanoelectrical transduction channels by means of the 'tip links' that connect stereocilia to one another. This paper reports the composition of mammalian tip links cadherin 23 and protocadherin 15 and show how the two molecules interact. Interestingly, mutation of these cadherins causes deafness in humans.

The CMS Collaboration reports the study of three simultaneous hard interactions between quarks and gluons in proton–proton collisions. This manifests through the concurrent production of three J/ψ mesons, which consist of a charm-quark–antiquark pair.

Acquired resistance to immunomodulatory drugs is common in multiple myeloma patients, but rarely attributed to genetic alterations. Here, proteomic, phosphoproteomic and RNA sequencing analysis in five paired pre-treatment and relapse samples reveals a CDK6-regulated protein resistance signature.

Female subfertility is highly associated with endometriosis. Here the authors show that progesterone-induced MIG-6 is reduced in endometrium of infertile women and non-human primates with endometriosis, and in a mouse model find that Erbb2 is the key mediator of Mig-6 loss induced endometriosis-related infertility.

In this largest whole-exome sequencing study of epilepsies to date, the Epi25 Collaborative identified extremely rare variants that confer risk for diverse epilepsy subtypes, highlighting roles in synaptic transmission and neuronal excitability.

The most up-to-date combination of results on the properties of the Higgs boson is reported, which indicate that its properties are consistent with the standard model predictions, within the precision achieved to date.

The CMS Collaboration reports evidence for off-shell Higgs boson contributions in the production of Z boson pairs, and measures the width of the Higgs boson, which is inversely related to its lifetime.

Ribosome biogenesis is tightly coordinated with cell-cycle progression. By characterizing the SUMO isopeptidases SENP3/SENP5, Doenig et al. identify a long-sought p53-independent impaired ribosome checkpoint that converges on downregulation of CDK6.

Age impacts the effect of dietary health and longevity interventions but the underlying mechanisms are incompletely understood. Here the authors study fasting in killifish and find that older animals exhibit a metabolic shift resembling a fasting-like program, which is counteracted by boosting the activity of AMPKγ1, promoting health and longevity.

Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

Age at onset of X-linked dystonia-parkinsonism is 50% explained by the length of a repeat in an SVA insert. The authors perform a GWAS for genetic modifiers and discover three more loci, accounting for another 13% of variability in age at onset with the protective alleles delaying onset by seven years.

Inferring other people’s intentions from their actions is essential for successful social engagement. Here, the authors show that in social contexts, dopamine D2 receptors are important in regulating uncertainty-driven belief updating.

Astrocytes play important roles in neuroinflammatory diseases. Here the authors characterize human glioblastoma-associated astrocytes by gene expression and demonstrate their immunosuppressive role promoted by interactions with tumor and microglia cells in an organotypic model.

Genome-wide association meta-analyses identify 26 risk loci for epilepsy, including 19 loci specific to genetic generalized epilepsy. Prioritized candidate genes implicate synaptic processes and overlap with targets of antiseizure medications.

Sinonasal tumour diagnosis can be complicated by the heterogeneity of disease and classification systems. Here, the authors use machine learning to classify sinonasal undifferentiated carcinomas into 4 molecular classe with differences in differentiation state and clinical outcome.

Proteasomal degradation of EZH2 in AML patients in response to therapy triggers the expression of stem cell markers and has been identified as an epigenetic pathway leading to acquired drug resistance. Treatments aimed to restore EZH2 expression in relapsed AML patients have shown clinical efficacy and constitute a viable approach to re-sensitize tumors to chemotherapy.

Asian soybean rust caused by Phakopsora pachyrhizi is an important plant pathogen, but an accurate genome assembly for this fungus has been lacking. This study sequenced three independent P. pachyrhizi isolates and generated reference quality assemblies and genome annotations, representing a critical step for further in-depth studies of this pathogen and the development of new methods of control.

The bacterial Hsp70 chaperone system consists of DnaJ, DnaK and GrpE. To understand how these chaperones cooperate, Nunes et al. monitor refolding immunoglobulin domains using single-molecule force microscopy to demonstrate that the ‘holdase’ DnaJ can show foldase activity and suggest that GrpE can facilitate substrate release from DnaK.

RNA polymerase (Pol) I transcribes ribosomal RNA that is critically required for ribosome assembly, and the enzyme is a major determinant of protein biosynthesis and cell growth; here the crystal structure of the complete 14-subunit Pol I from yeast is determined, providing insights into its unique architecture and the possible functional roles of its components.

Animal lifespan is plastic and is regulated by conserved signalling pathways. Here, Tikuet al.show that longevity-enhancing mutations or interventions are associated with reduced nucleolar size in worms, flies, mice and humans, and that nucleolar size can predict life-expectancy in individual worms.

Corticobasal degeneration is a rare neurodegenerative disorder that can only be definitively diagnosed by autopsy. Here, Kouri et al. conduct a genome-wide-association study and identify two genetic susceptibility loci 17q21 (MAPT) and 3p12 (MOBP), and a novel susceptibility locus at 8p12.

In this Opinion, Burkhard Hense, Jan-Ulrich Kreft and colleagues discuss quorum sensing and diffusion sensing, an alternative explanation for autoinducer signalling, and the problems they feel are associated with each explanation, before going on to propose efficiency sensing as a unifying functional hypothesis.

The recognition of histone post-translational modifications by effector modules such as bromodomains is a key step in many chromatin-related processes. Although effector-mediated recognition of single post-translation modifications is well characterized, combinatorial readout of histones bearing multiple modifications is poorly understood. Here, a distinct mechanism of combinatorial readout for the mouse TAF1 homologue Brdt, a testis-specific member of the BET protein family, is reported.

The mechanisms underlying adaptation of bacteria to changing environmental conditions remain poorly understood. Here, the authors show bacteria using lysine acetylation of transcriptional regulators to adjust gene expression to changing conditions.

Coupling advances in socioeconomic projections, climate models, damage functions and discounting methods yields an estimate of the social cost of carbon of US$185 per tonne of CO₂—triple the widely used value published by the US government.

In a phase I/II dose-escalation clinical trial, the mRNA COVID-19 vaccine BNT162b1 elicits specific T cell and antibody responses that suggest it has protective potential.

Hearing loss, which is caused by both genetic and environmental factors, is the most common form of sensory impairment in humans. Current treatment relies on medical devices and there are no drug-based therapies available. Here, Müller and Barr-Gillespie review the various forms of hearing loss, highlight emerging pharmacological targets and discuss the potential of regenerative medicine and gene therapy to restore auditory function.

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.

Predicted responses to climate change may be informed by evolutionary history. Here, the authors reconstruct the phylogeny of lacertid lizards and investigate how the evolution of this clade has varied with paleoclimates and how closely adapted extant species are to modern climates.

Here, using an integrative experimental and computational approach, Imle et al. show how cell motility and density affect HIV cell-associated transmission in a three-dimensional tissue-like culture system of CD4⁺ T cells and collagen, and how different collagen matrices restrict infection by cell-free virions.

Maintenance and quality control of the mitochondrial respiratory chain complexes responsible for bulk energy production are unclear. Here, the authors show that the mitochondrial protease ClpXP is required for the rapid turnover of the core N-module of respiratory complex I, which happens independently of other modules in the complex.

The interaction between TASL and SLC15A4 links endolysosomal Toll-like receptors to the transcription factor IRF5, providing a mechanistic explanation for the involvement of the complex in systemic lupus erythematosus.