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A technique for the site-directed conjugation of antibodies via the small-protein ubiquitin allows for the efficient multivalent conjugation of antibodies and nanobodies to fusions of ubiquitin with molecular or proteinic moieties.

Opioid use impacts metabolic homeostasis, although the mechanisms remain elusive. Here, the authors explore the OPRD1 gene (encoding the delta opioid receptor, DOP) to understand its impact on type 2 diabetes and highlight DOP as a key player between opioids and metabolic homeostasis.

Small heat shock proteins (sHsps) contribute to cellular recovery and survival following stress causing elevated levels of misfolded or unfolded proteins. Here the authors demonstrate that sHsps function by maintaining aggregating proteins in close-to-native conformations to facilitate chaperone-mediated refolding.

JMML is an aggressive hematologic malignancy with myeloproliferative characteristics affecting young children. Here the authors report that C-type lectin-like molecule-1 (CLL-1) is upregulated in JMML and they develop CLL-1 CAR T cells showing in vitro and in vivo anti-JMML activity.

The γ-TuRC plays a key role in regulated nucleation of microtubules (MTs). Here, the authors reveal how yeast γ-TuRC is assembled and activated by dimeric CM1 motifs in receptor protein Spc72 and how MT polymerase Stu2 binds to promote MT assembly.

How gut microbiota affect systemic responses to viral infection is still unclear. Here the authors use LCMV mouse infection model to show that a low complexity 12-strains community but not germ-free condition potentiates anti-viral immunity against LCMV beyond that of specific pathogen-free mice, but also aggravates LCMV-induced diseases.

RNA-guided CRISPR-associated transposases (CAST) are natural systems with broad potential in biotechnology. Here, the authors report compact type V-K CAST discovered from genome-resolved metagenomics and demonstrate targeted integration of a large transgene to a safe-harbor site in the human genome.

Multiple myeloma disease progression and therapy response are influenced by the bone marrow niche in which the tumor cells reside. To characterize this supportive niche, Cupedo and colleagues use single-cell transcriptomic analysis of bone marrow stromal cell populations from individuals with multiple myeloma. They identify a myeloma-specific inflammatory mesenchymal stromal cell (iMSC) population that spatially colocalizes with tumor cells. Anti-myeloma induction therapy does not influence iMSC presence, suggesting a role for bone marrow inflammation in myeloma persistence or relapse.

The acidophilic fungus Acrodontium crateriforme is present in traps of the carnivorous plant Drosera spatulata and promotes prey digestion.

In this study, the authors identify genetic insertions in the population of hepatitis E virus analyzed in serum samples of a patient with ribavirin treatment failure. They show that these genomic rearrangements promote viral replication without affecting ribavirin sensitivity.

The efficacy of T-cell-based cancer immunotherapies can be compromised by T cell exhaustion. Here the authors develop a human ex vivo exhaustion model and, based on a CRISPR-Cas9 screen, identify SNX9 as a regulator of T cell exhaustion, showing that SNX9 knockout is associated with improved T cell function and anti-tumor activity in preclinical cancer models.

Pathogenic germline variants in TP53 predispose to a variety of cancers, but variants solely affecting alternatively spliced isoforms of TP53 are understudied. Here, the authors identify a heterozygous stop-lost variant that specifically affects p53β isoforms and predisposes to familial cancer using germline whole-exome sequencing and functional genomics assays.

A multidimensional proteomics analysis of the interactions between around 2,000 nuclear proteins and over 80 modified dinucleosomes representing promoter, enhancer and heterochromatin states provides insights into how chromatin states are decoded by chromatin readers.

The authors uncover the roles and regulations of DNA polymerase κ (Polκ) during DNA damage bypass. In addition to a catalytic function across minor groove DNA lesions, Polκ stimulates Polζ-mediated extension past various DNA lesions.

A live-attenuated SARS-CoV-2 vaccine based on one-to-stop codon modifications can elicit broad, systemic and mucosal immunity, as well as reduced transmission of SARS-CoV-2 in vivo.

Arrayed and pooled high-throughput screening is crucial for drug discovery and CRISPR functional genomics. Here, the authors present dFLASH; a dual FLuorescent transcription factor Activity Sensor for Histone-integrated live-cell reporting for high performance screening applications across numerous pathways and screening contexts.

Mitochondrial DNA or retrotransposon cDNA released into the cytoplasm is degraded to prevent sterile inflammation. In this study, the authors demonstrate that nucleolytic degradation of these DNA species in a yeast model organism prevents their transfer to the nucleus and genome instability.

Interactions between germline variants and somatic mutations is a relatively unexplored topic in cancer. Here, in Ewing sarcoma, the authors show that binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancer-like DNA element controls MYBL2, whose high expression correlates with prognosis.

CRISPR-Cas9 generates double-strand breaks, which pose a threat to genome integrity. Here the authors show loss of heterozygosity in edited hematopoietic progenitor cells.

The control of flagellar synthesis and function in the Lyme spirochete Borrelia burgdorferi is poorly understood, as this pathogen lacks the typical flagellar sigma factor and transcriptional regulators. Here, the authors identify a broadly conserved structural flagellar component that modulates flagellar assembly and is important for cell division, motility and virulence.

Within the previous framework of jamming, granular systems were expected to jam only above a critical density, but here it is shown that application of shear to frictional grains can lead to a rich set of anisotropic jammed states at densities below this critical value.

ON-target genotoxicity in gene editing is generally underestimated. Here the authors report Fluorescence-Assisted Megabase-scale Rearrangements Detection (FAMReD) systems to detect and characterize rare large loss of heterozygosity: they show that ON-target genotoxicity can be prevented by p53 and cell cycle arrest.

A quantitative atlas of the transcriptomes, proteomes and phosphoproteomes of 30 tissues of the model plant Arabidopsis thaliana provides a valuable resource for plant research.

The bacterial flagellum is a complex macromolecular structure that requires a highly regulated assembly of building blocks. Here, Halte et al. show that a protein controls assembly of the flagellum’s periplasmic rod and prevents misformation of flagella in the periplasm.

A candidate vaccine against SARS-CoV-2 that uses the yellow fever 17D live-virus vector is highly efficacious and displays a favourable safety profile in Syrian hamster, mouse and cynomolgus macaque models.

The RNAse III endonuclease Dicer is crucial for processing of pre-miRNAs in health and disease. Here the authors show that endothelial Dicer promotes atherosclerosis by increasing miR-103 levels leading to suppression of the anti-inflammatory transcription factor KLF4, thus suggesting a novel approach to treat this disease.

Removing the large inverted repeat region from the chloroplast genome revealed a gene dosage benefit for the ribosomal RNA operon. The reduced genome size resulted in increased genome copy numbers and offers potential for synthetic biology.

Retinoic acid is known to be effective against bone marrow metastatic neuroblastoma cells, but not primary tumors. Here, authors discover that bone morphogenetic protein signaling is responsible for determining neuroblastoma cell fate and sensitivity to retinoic acid.

Unconventional protein secretion emerges as an important mechanism in aggregate-prone protein removal. Here, the authors demonstrate that Plekhg5 mediates the unconventional secretion of Sod1 by presynaptic secretory autophagy.

Shen et al. report a method for multiplexing isogenic iPSCs for single-cell RNA-seq. With it, they created an atlas of in vitro differentiation and identified TMEM88 as a regulator of cardiovascular development, impacting blood pressure in adult mice.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

Mpox virus productively infects human induced pluripotent stem cell-derived skin organoids and is inhibited by tecovirimat, revealing a model system for analysis of mpox virus pathogenesis and drug screening.

Outer membrane tethering is important for cell envelope integrity in diderm bacteria. Here, the authors present structures and functional analyses of the stalked porin OmpM, which is the main outer membrane tethering system within the Terrabacteria.

The Candida albicans toxin, candidalysin, is embedded in an unusual conserved precursor peptide sequence (Ece1). The precursor is not required to block premature pore-forming toxicity, but rather to prevent candidalysin auto-aggregation.

An assessment of variations in phytoplankton nutrient limitation in the tropical Pacific over the past two decades finds that phytoplankton iron limitation is more stable in response to ENSO dynamics than models predict.

Using data from the Tara Pacific expedition, this study reports the biogeography and the diversity of microbiomes collected from corals, fish and plankton in 99 reefs across the Pacific Ocean. The large richness of Pacific Ocean reef microorganisms, when extrapolated to all fish and corals of the Pacific, represents the current estimated total prokaryotic diversity for the entire Earth.

The role of mutations within long noncoding RNAs (lncRNAs) exons on tumour cell fitness remains to be explored. Here, the authors investigate the landscape of driver lncRNAs in primary and metastatic samples and validate the functional significance of single nucleotide variants in the NEAT1 oncogene in vitro and in vivo.

Anisimov, Fang et al. report that in humans, genetic variants associated with higher TIE2 expression are predicted to confer a reduced risk of CAD; in mice, Tie2 expression in endothelial cells is atheroprotective, and in a subset of aortic fibroblasts, anti-inflammatory.

Synaptic activity controls the extinction of conditioned fear. Here the authors discovered a new way that the brain controls memories of fear: a long noncoding RNA called Gas5 that coordinates the activity of RNA granules in the synaptic compartment.

CAR-T therapy is a promising treatment modality for B-cell malignancies, yet many patients relapse. Using an in vivo genomewide screen in a model of B cell leukemia, we identify an unexpected mechanism of CAR-T resistance in which interferon gamma from the in vivo tumor microenvironment induces an adaptive T-cell resistance program in tumor cells.

SPI1 fusion genes in T-cell acute lymphoblastic leukemia (T-ALL) are commonly found with co-occurring NRAS mutations. Here, the authors show that the combination of these oncogenes is necessary to drive T-ALL in a murine model and that the oncogenic activity of the SPI1 fusion is dependent on β-catenin.

Mucosal surfaces of the respiratory tract are the first sites of entry and defense against SARS-CoV-2. Di Santo and colleagues perform paired analysis of the nasopharyngeal and systemic immune responses of SARS-CoV-2-infected patients and demonstrate distinct compartmentalization of immunity and shifts in the microbiome.

Variants of the 3′−5′ exonuclease TREX1 can cause retinal vasculopathy with cerebral leukoencephalopathy (RVCL). Here, the authors show that RVCL-associated TREX1 variants trigger DNA damage in humans, mice, and Drosophila, and render cells more vulnerable to DNA damage inducing agents.