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Knockout studies using CRISPR–Cas9 identify PCDH10 as a selective host cellular receptor for western equine encephalitis virus.

Peptidoglycan biosynthesis is regulated by a feedback mechanism preventing the pathway from sequestering essential lipid carriers used to assemble and transport surface glycan subunits.

Shaw et al identify the neonatal Fc receptor (FcRn) as a host factor required for infection of cells by several divergent arteriviruses, and demonstrate that anti-FcRn antibodies can be used to block arterivirus infection.

This protocol leverages tailored adeno-associated virus vectors for effective delivery of pooled CRISPR-based genetic perturbations in live animals combined with single-cell gene expression readout of phenotypic effects.

Cryo-EM has facilitated structural studies of membrane proteins, but inactive GPCRs have remained inaccessible due to their small size. Robertson et al. demonstrate a common nanobody-based approach to streamline the determination of such structures.

A hyper-stable de novo protein mimic of interleukin-2 computationally designed to not interact with a regulatory T-cell specific receptor subunit has improved therapeutic activity in mouse models of melanoma and colon cancer.

Whilst SARS-CoV-2 mRNA vaccines have demonstrated efficacy in reducing infection severity, research has shown that SARS-CoV-2 infection is associated with new autoantibodies. Whether this would also be observed during mRNA vaccination is unclear. Here, the authors use an autoantibody screening platform to monitor autoantibody responses in a diverse cohort during vaccination.

Utilising proteomic and transposon sequencing screens, Freiberg et al. identified arginine metabolism enzymes that impact tolerance to antibiotics in Staphylococcus aureus, including in animal models of skin and bone infections.

Izar and colleagues demonstrate that loss of Pip4k2c in melanoma cells promotes liver metastatic tropism driven by PI3K-AKT pathway activation in the insulin-rich liver milieu, which can be abrogated by inhibition of SGLT2 or a ketogenic diet.

Rapid extracellular antigen profiling of a cohort of 194 individuals infected with SARS-CoV-2 uncovers diverse autoantibody responses that affect COVID-19 disease severity, progression and clinical and immunological characteristics.

Mice bearing different variants of APOE exhibit different COVID-19 outcomes, with APOE2 and APOE4 associated with more severe disease, and this relationship between APOE genotype and disease severity is supported by clinical data in humans.

Optimization of monoclonal antibodies against SARS-CoV-2 for enhanced Fc-effector function increase their effectiveness for prevention and treatment of COVID-19 in multiple animal models of SARS-CoV-2 infection.

A class of compounds with a dual mechanism of action—direct targeting of IspH and stimulation of cytotoxic γδ T cells to enhance pathogen clearance—are active against multidrug-resistant bacteria.

A population of spinal interneurons that form axo–axonic connections with the terminals of proprioceptive afferents are shown to mediate presynaptic inhibition; their ablation elicits harmonic oscillations during goal-directed forelimb movements, which can be modelled as the consequence of an increase in sensory feedback gain.

Although rare, antibodies against the receptor-binding domain of SARS-CoV-2 that showed potent antiviral activity were obtained from all tested convalescent individuals, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.

Understanding principles of neuronal connectivity requires tools for quantification and visualization of large datasets. Here, the authors introduce an online resource encompassing the coordinates of two million neurons labelled by tracer injections in the marmoset cortex, and analysis tools.

The crystal structure of anion channelrhodopsin-1 (ACR1) from the algae Guillardia theta provides insights into the basis of anion conductance.

Cryo-EM structures of human calcium-sensing receptor reveal intrinsic asymmetry in the receptor homodimer upon activation that is stabilized by calcimimetic drugs adopting distinct poses in the two protomers, priming one protomer for G-protein coupling.

The molecular mechanism underlying the severe neurogenic inflammation induced by Clostridioides difficile is presented, providing a therapeutic target for treating this infection.

ESR1-expressing cells in the principal nucleus of the bed nucleus of stria terminalis are necessary, sufficient and naturally activated during infanticide, and they form reciprocal inhibition with the maternal cells to control young-directed behaviours in female mice.

Derek Mann and his colleagues have found that experimental induction of liver fibrosis in male rats results in an epigenetic modification of the chromatin in their sperm such that their offspring have a more mild wound-healing response to hepatic fibrogenic insults. The mechanism responsible for this phenomenon is not clear, but it seems to involve a yet unidentified soluble factor released by myofibroblasts that act on either the germ cells or mature sperm.

Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.

A longitudinal analysis of immune responses in patients with moderate or severe COVID-19 identifies a maladapted immune response profile linked to severe disease.

A cryo-electron microscopy structure of β-arrestin 1 in complex with the M2 muscarinic receptor reconstituted in lipid nanodiscs is reported.

X-ray and cryo-electron microscopy structures of fungal mitochondrial calcium uniporter proteins reveal a tetrameric architecture and shed light on the function of the channel.

Organoids derived from human intestinal cells that are co-cultured with bacteria carrying the genotoxic pks⁺ island develop a distinct mutational signature associated with colorectal cancer.

Cryo-electron microscopy structures of GPR56 and latrophilin 3 show how the released tethered agonist peptide interacts with the transmembrane domain, suggesting a model for the activation mechanism of adhesion G-protein-coupled receptors.

Immune analyses against circulating SARS-CoV-2 variants show that mRNA vaccination induces robust neutralizing antibodies and boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection.

Personalized neoantigen vaccination in patients with melanoma elicits durable and specific memory T cell clones that have cytotoxic gene signatures and can diversify to include nonvaccine neoantigen specificities.

An improved, single-cell lineage-tracing system, based on deep detection of naturally occurring mitochondrial DNA mutations with simultaneous readout of transcriptional states and chromatin accessibility, is used to define the clonal architecture of haematopoietic stem cells.

Human fibroblasts undergo conversion to angioblast-like progenitors and then to endothelial cells by brief exposure to pluripotency factors, which is then followed by differentiation.

Here, the authors identify and validate the emergence of a SARS-CoV-2 resistance mutation to Remdesivir, associated with virological recrudesce in an immunocompromised patient with persistent COVID-19.

Todd et al. show a daily rhythm in aggression propensity in male mice and reveal a novel polysynaptic circuit within the hypothalamus by which the central circadian clock (the suprachiasmatic nucleus) influences neurons that regulate attack behavior.

The authors identify Drosophila cGLR1 as a double-stranded RNA sensor and 3′2′-cGAMP as a nucleotide second messenger and activator of Drosophila STING signalling.

Magnetically confined neutral antihydrogen atoms released in a gravity field were found to fall towards Earth like ordinary matter, in accordance with Einstein’s general theory of relativity.

The crystal structure of the mouse μ-opioid receptor bound to an antagonist is described, with possible implications for the future development of analgesics.

Despite effective vaccines against SARS-CoV-2, therapeutic options such as anti-virals and neutralizing antibodies are critical in treating disease, especially given the breakthrough infections of emerging VOCs. Here, Peng et al. generate two potent monoclonal antibodies and a bispecific antibody with two antigenrecognition variable regions targeting SARS-CoV-2 spike, provide CryoEM structures and show in vitro and in vivo efficacy of a humanized antibody against wildtype virus and delta variant.

Activated clonally expanded CD4⁺ T cells display specificity to the myelin peptide MOG, whereas clonally expanded CD8⁺ T cells depend on T cell receptor recognition of unrelated surrogate peptides and have a regulatory function.

Synthetic chimeric orthogonal IL-2 receptors that incorporate the intracellular domain of receptors for other γ-chain cytokines such as IL-9 can reroute orthogonal signalling and alter the phenotype of T cells to improve anti-tumour responses.

Crystal structures and molecular simulations of the designed anion-conducting channelrhodopsin iC++ provide molecular insights that enable structure-based design of channelrhodopsins with desirable properties for use as optogenetic tools.

X-ray crystallography and molecular dynamics simulations of the μ-opioid receptor reveal the conformational changes in the extracellular and intracellular domains of this G-protein-coupled receptor that are associated with its activation.

Convalescent plasma (CP) has been trialed as a therapy for SARS-CoV-2 symptoms, but its heterogenous nature precludes uniform outcomes. Here the authors perform deep profiling of CP, as well as plasma of CP recipients before and after transfer, to find CP-mediated, spike/nucleocapsid-focused modulations of humoral responses in the recipient.

Recent studies have shown that human induced pluripotent stem cells contain point mutations in coding regions, but the functional significance of these mutations is unclear. Here the authors provide evidence that these mutations are unlikely to confer a selective advantage for reprogramming.

Glioblastoma is a deadly brain tumor with no cure. The cytokine receptor OSMR is identified as a new key player in glioblastoma pathogenesis. OSMR orchestrates a feed-forward mechanism with the oncogenic protein EGFRvIII and the transcription factor STAT3 to drive oncogenesis. Loss of OSMR impairs EGFRvIII-STAT3 signaling and glioblastoma tumorigenesis.

A method to accelerate the generation of kidney organoids from human pluripotent stem cells cultured in a three-dimensional environment and exposed to inductive stimuli has been developed, with the organoids capable of recapitulating kidney organogenesis.

A long-term culture method for organoids derived from single adult human lung cells is used to identify progenitor cells and study SARS-CoV-2 infection.

CRISPR–Cas9 genome editing is used to induce a DNA repair response and correct a disease-causing heterozygous mutation in human embryos with reduced mosaicism and preferential repair using the wild-type copy of the gene.

Chris Garcia, David Baker and colleagues use a computational approach to develop designed repeat protein binders (DRPBs), which function as human Frizzled (Fz) subtype-selective antagonists and enable identification of Fz subtypes active in different organs.