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Differentiating between wild and domesticated South American camelids in the archaeological record can be challenging. Here, the authors use aDNA to infer ancestry of 49 camelids from the South-Central Andes (3,360–2,370 cal. yr BP), finding that most were not ancestors of living camelids and were likely wild, hunted camelids or herded camelids with selective male culling.

Somatically determined preferential allelic expression of select genes that when mutated cause inborn errors of immunity corresponds with disease phenotypes, suggesting that the penetrance and expressivity of monogenic disorders is also dependent on the ‘transcriptotype’.

An analysis of 38 ancient genomes from the aurochs, the extinct ancestor of modern cattle, provides insight into the population ancestry and domestication of this species.

Engineered two-component signalling proteins in Escherichia coli have residue specificities different to their parent proteins and are orthogonal to all extant paralogues, demonstrating that sequence space is not densely occupied.

Current electrochemical-based protein labelling methods suffer from limited site-selectivity and off-target reactivity owing to required radical/electrophilic reagents. Now an electrochemical strategy enables chemoselective labelling of proteins at a site-specifically incorporated 5-hydroxytryptophan residue using aromatic amines as coupling partners. This approach works on various proteins, including a full-length antibody, and is compatible with established click reactions.

Raman spectroscopic imaging (RSI) can provide information on the chemical composition of a sample, but application to living organisms has lacked sufficient spatial resolution and signal strength. Here the authors apply confocal RSI to whole-mount zebrafish embryos to distinguish different infectious bacteria and to living zebrafish embryos to monitor the wound healing process.

Aetiology of colitis is highly complex and incompletely understood. Here the authors show in mouse models that A20 deubiquitinase limits pro-inflammatory cytokine production in myeloid cells while inhibiting proapoptotic response to these cytokines in enterocytes, and that only upon losing both functions intestinal pathologies develop.

ABCC9 encodes the SUR2 subunit of K_ATP channels and dominant genetic variants in ABCC9 have been associated with cardiac phenotypes. Here, the authors report recessive ABCC9 mutations in individuals with mild intellectual disability, myopathy and cardiac systolic dysfunction which is associated with loss of K_ATP channel function.

Mucopolysaccharidoses (MPS) are inherited metabolic disorders caused by enzyme deficiencies leading to glycosaminoglycan accumulation and systemic degenerative disease. Here, the authors show that iPSC-derived microglia progenitors can reduce glycosaminoglycan accumulation and prevent behavioral deficits in MPS mouse models.

Climate change effects on wildlife may occur through both gradual changes and extreme events. Here, the authors quantify the impact of cold snaps and heatwaves on reproductive success in 24 common bird species in North America over the last few decades.

IL-10 can limit inflammation in part by inhibiting miR-155. Here the authors show how this axis induces mitochondrial arginase-2 to alter the mitochondrial dynamics and bioenergetics of macrophages and make these cells less pro-inflammatory.

A study presents a strategy based on human pluripotent stem cells for treating neurodegenerative disorders of the gastrointestinal tract.

Nicholas Payne et al. use physiological and population-level abundance data from 823 fish species to examine how heating tolerance scales at both the individual and population level. This study shows that heating tolerance declines in the lab and the wild at the same rate, and for a given temperature, individuals and populations from tropical areas have broader heating tolerances than temperate species.

Randolph and colleagues analyze the immune cells in the human and mouse peritoneum and show that the major populations of serous cavity-resident macrophages in humans and mice represent distinct differentiation stages of an overlapping differentiation program.

Using voltage imaging, the authors show that interneurons in the hippocampus sharpen memory-encoding-activity by increasing the signal-to-noise ratio of pyramidal neuron sensory representations during working memory in mice.

The authors reveal the complex interplay of factors influencing climate-related body-size changes in tree swallows. Nest warming increased chick size and success yet adult structural size decreased, and mass of males decreased but females did not, the latter linked to reproduction trade-offs.

Screening for new anthelmintic compounds that are active against parasitic nematodes is costly and labour intensive. Here, the authors use the non-parasitic nematode Caenorhabditis elegansto identify 30 anthelmintic lead compounds in an effective and cost-efficient manner.

Nail-patella syndrome (NPS) is characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma and can be caused by haploinsufficiency of LMX1B; however, not all patients harbor pathogenic LMX1B mutations. Here the authors show that loss-of-function variations in upstream enhancer sequences are responsible for a limb specific form of human NPS.

The ASAP4 family of genetically encoded voltage indicators allows recording of action potentials and subthreshold activity with either one- or two-photon microscopy over extended periods of time.

Isolated human and mouse enteric nervous system stem cells (ENSCs) are capable of integrating and promoting innervation of the mouse colon. Here the authors show that transplantation of mouse ENSCs into a mouse model of human enteric neuropathy restores colon motility.

Cancers often harbor mutations in genes encoding important regulatory proteins, but therapeutic targeting of these molecules proves difficult due to their high structural similarity to their non-mutated counterpart. Here authors show the engineering of T cell engaging bispecific protein able to selectively target cancer cells with a high-frequency mutation in the KRAS oncogene.

The ability to design functional sequences is central to protein engineering and biotherapeutics. Here the authors introduce a deep generative alignment-free model for sequence design applied to highly variable regions and design and test a diverse nanobody library with improved properties for selection experiments.

Aarrestad et al. show that, in contrast to psychedelics, the nonhallucinogenic psychoplastogen tabernanthalog promotes neuroplasticity through 5-HT_2AR activation without immediately increasing extracellular glutamate levels or immediate early gene expression.

BilR is identified as a bilirubin reductase encoded by gut bacteria, which reduces bilirubin to urobilinogen.

A nonlinear microscopy method identifies a fluorescent signature consistent with the early signs of calcification in animal and human aortic valves.

The ribosome-associated quality control complex (RQC) functions to disassemble stalled ribosomes. Here the authors find that the tRNA hydrolase Vms1 is involved in the release of nascent peptide from stalled ribosomes.

The autophagy protein p62 undergoes liquid-liquid phase separation but how this is regulated is unclear. Here, the authors report that the histone chaperone DAXX interacts with p62 in the cytoplasm to drive its phase separation.

The stability of epithelial adherens junctions depends on tension generated by actomyosin contractility. Here Lee et al. describe a novel role for the axon guidance receptor Neogenin in maintaining junctional stability by recruiting actin nucleation machinery to adherens junctions.

A newly developed maternally selective nanobody antagonist against the angiotensin II type I receptor stabilizes the receptor in a hybrid conformation and simultaneously binds with specific small-molecule antagonists.

RNA-Seq analysis of an 8-year longitudinal study of long-lived bats reveals unique transcriptomic signatures and novel candidate genes associated with healthy ageing.

Autonomous hypermutation yeast surface display (AHEAD) mimics the process of somatic hypermutation in animals to enable the rapid in vitro evolution of antibodies, including nanobodies targeting the RBD of SARS-CoV-2.

Using ovarian and breast cancer models, Barkal et al. identify CD24 as a novel anti-phagocytic ‘don’t eat me’ signal on tumour-associated macrophages that orchestrates an innate immune checkpoint to modulate antitumour immunity, highlighting the promise of CD24 blockade as an immunotherapy strategy.

Kamerkaret al. have engineered exosomes that target KRAS^G12D(iExosomes) and have demonstrated the specificity and efficacy of iExosomes in targeting oncogenic KRAS in mouse models of pancreatic cancer.

A natural product containing an acylsulfenic acid functional group was discovered in a marine Streptomyces bacterium. Its biosynthesis is orchestrated by enzymes from both primary and secondary metabolism, including a flavin-dependent S-hydroxylase. The prevalence of enzymes catalysing the production of acylsulfenic acid in bacteria implies a potentially broad distribution of this functional group in specialized metabolites.

The mechanisms underlying epilepsy development are not well understood. Here the authors show that loss of a key component of the so called blood-brain barrier drives seizures in mice and is also lost in humans with treatment resistant epilepsy

Human ubiquitin E3 ligase E6AP contains a Zn-binding AZUL domain. Here the authors identify and name RAZUL, a domain in proteasome substrate receptor hRpn10 that binds AZUL, recruiting E6AP to proteasomes, and they present the NMR structure of the RAZUL:AZUL complex, which forms an intermolecular 4-helix bundle.

Here, the authors use cryo-EM, biochemical and yeast assays of the HAT NuA4–Tip60 to reveal its mechanism of acetylating distant nucleosomes through the Epl1 linker establishing long-range chromatin interactions.

This study finds that CRISPR-knockout phenotypes from genome-wide screens systematically show increased similarity to knockouts of unrelated genomically proximal genes located on the same chromosome arm. Multiple lines of evidence suggest that this proximity bias is caused by telomeric truncations of chromosome arms and is consistent across cell types, labs and Cas9 delivery methods.

The molecular dynamics associated with neuronal activation patterns in vivo are unclear. Lacar et al. perform single-nuclei RNA-sequencing of hippocampal neurons from mice exposed to a novel environment, and identify large-scale transcriptome changes in individual neurons associated with the experience.

The mechanism by which ingested material accesses the cytosol for cross-presentation is unclear. Caetano Reis e Sousa and colleagues demonstrate that signaling via the lectin receptor DNGR-1 ruptures the phagosome and releases its contents to the cytosol for cross-presentation.

Dysregulated immune features in a patient with a homozygous loss-of-function mutation in PDCD1 suggest that IL-6, IL-23, STAT3 and RORγT might be potential targets for treatment of PD-1 blockade-induced autoimmunity.

Here, a sparse neuronal projection from a part of the prefrontal cortex, the anterior cingulate, to the hippocampus is identified that, when activated, can elicit memory retrieval in mice.

Flexible fear-related responses may be advantageous in adolescence. Here the authors use microprisms to image prefrontal cortical spine maturation across development and report that plasticity in adolescent fear extinction responses is associated with dynamic reorganization in the amygdalahippocampal-PFC circuit.