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Melanoma cells lacking SOX10 are tolerant to MAPK inhibition (MAPKi) due to elevated TAZ-driven TEAD signaling. Here, the authors develop two inhibitors of TEAD, capable of resensitising SOX10 knockout melanoma cells to MAPKi and offering a strategy to overcome drug tolerance and improve treatment response.

Small cell lung cancer cells form functional synapses with glutamatergic neurons, receiving synaptic transmissions and deriving a proliferative advantage from these interactions.

Spatial transcriptomic studies and lineage tracing reveal that, after brain injury, transient profibrotic fibroblasts develop from existing brain fibroblasts, infiltrate lesions, regulate the local immune response and lead to beneficial scar tissue formation.

Formation of the energy-producing machinery in the proximal tubule of the nephron is an essential step in differentiation. The authors show that mitochondrial localization depends on LRRK2, the activity of which is modulated by fluid flow.

A neural implant with a subnanolitre-volume can provide year-long in vivo recordings in awake mice.

An understanding of the molecular mechanisms promoting the generation of immunoregulatory and tumour-promoting monocytes and macrophages is key to breaking the cycle of tumour myelopoiesis and developing more effective myeloid-targeting therapies.

Majzner and colleagues show that engineering T cells with a membrane-tethered version of the signaling adaptor molecule SLP-76 alongside a chimeric antigen receptor (CAR) enhances CAR T cell activity against low-antigen-density tumors.

Telomere-to-telomere assemblies of two mouse inbred strains, C57BL/6J and CAST/EiJ, offer improvements over the current mouse reference genome by adding telomere and centromere sequences that lead to insights into variability in telomere and centromere sizes and organization, and the discovery of 225 and 355 new genes for C57BL/6J and CAST/EiJ, respectively.

Myeloid-specific mechanotransduction ablation downregulates pro-fibrotic fibroblast transcriptional profiles to reduce scar formation in human cells

Human MATE1 is a key transporter in kidney and liver drug clearance. Here, authors present cryo-EM structures of MATE1 in complex with substrates and an inhibitor, revealing the structural basis of drug recognition.

Heart development and function rely on communication among diverse cardiac cells. Here, the authors show that RNF20 safeguards endothelial cell identity and orchestrates heart morphogenesis and contractility by restraining TGF-β signaling and modulating angiocrine communication.

mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.

Weldy et al. show that smooth muscle expression of the RNA editing enzyme ADAR1 regulates activation of the double-stranded RNA sensor MDA5 in a novel mechanism of atherosclerosis.

Astrocytes drive multiple sclerosis (MS) by enhancing inflammation. Here, the authors show that the deubiquitinase OTUD7B in astrocytes protects mice from experimental autoimmune encephalomyelitis (EAE), a model of MS, by reducing inflammation and stabilizing GFAP thereby physically restricting inflammation.

Environmental factors such as diet have been shown to be involved with the development of colitis. Here the authors show that L-tryptophan promotes the development of GPR15⁺ Treg cells via the host IDO1/2 pathway and that tryptophan consumption in mice reduces severity of colitis in a C. rodentium mouse model.

KRAB-zinc finger proteins repress retrotransposons and rapidly evolve in mammals. Here, the authors show that ERV insertions drive the emergence and diversification of new KZFP genes in mice, revealing a co-evolutionary mechanism between retroviruses and host repressors.

Basal cells, rather than neuroendocrine cells, have been identified as the probable origin of small cell lung cancer and other neuroendocrine–tuft cancers, explaining neuroendocrine–tuft heterogeneity and offering new perspectives for targeting lineage plasticity.

The neuronal architecture that develops after spinal cord injury and causes autonomic dysreflexia is uncovered.

Genomic integration of DNA templates is made more precise through microhomology-focused design.

The authors find that TDP-43 loss of function—the pathology defining the neurodegenerative conditions ALS and FTD—induces novel mRNA polyadenylation events, which have different effects, including an increase in RNA stability, leading to higher protein levels.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

Imbalanced nucleotide metabolism leads to age- and mtDNA-dependent inflammatory responses and senescence-associated secretory phenotype in senescence.

High-density multimodal soft bioelectronic fibres provide a platform for minimally invasive implantable electronics, where diverse sensing and stimulation functionalities can be effectively integrated.

Severe febrile illnesses in children may be various in presentation and aetiology but involve immune dysfunction amenable to immunomodulation. Here, the authors identify shared neutrophil and T cell dysfunction and a distinct interferon signature in critically ill children with severe febrile illness.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

N-glycans on glycoRNAs prevent innate immune sensing of endogenous small RNAs, and the natural mechanism they use demonstrates how glycoRNAs exist on the cell surface and in the endosomal network without inducing autoinflammatory responses.

Cytoskeletal breakdown is a hallmark of synapse elimination. Here, the authors show that a post-translational modification on microtubules encodes activity-dependent signals instructing neuronal remodeling in the central and peripheral nervous system.

Zaman, Yang and Huang et al. demonstrate MDK’s suppressive effect on amyloid-β and its impact on amyloid burden and microglial activation in Alzheimer disease mice, highlighting its protective role in pathogenesis.

Previous research has suggested that pDCs are required for an effective antiviral immune response, but direct experimental evidence to support this is lacking. Here Ngo et al. develop a pDC knockin mouse model and find that pDCs are dispensable for an antiviral immune response to mouse cytomegalovirus and may be detrimental during influenza or SARS-CoV-2 infection.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Artis and colleagues show that enteric neurons produce CGRP-related ADM2 to promote intestinal tissue-protective functions in ILC2s.

Dendritic cells are supplied antigens by other cells such as lymphatic endothelial cells (LEC) at late time points after immunization. Here the authors show antigen archiving is defined by a transcriptional program that can predict antigen archiving depending on the priming pathogen, and that boosting of immune responses increases the archiving.

The International Brain Laboratory presents a brain-wide electrophysiological map obtained from pooling data from 12 laboratories that performed the same standardized perceptual decision-making task in mice.

The authors studied mice with targeted deletion of OPA1, a mitochondrial fusion protein, in intervertebral disc and knee articular cartilage, and showed that maintenance of mitochondrial dynamics is critical for the health of these hypoxic tissues

Conventional Dendritic cells (cDCs) continually migrate from peripheral tissues in homeostasis. Here, the authors analyse the homeostatic turnover of cDC subsets in the intestine from tissue entry to migration to the draining lymph nodes, noting a dynamic life cycle with changes in transcriptome and proliferation rates.

Shabanzadeh et al. identify and validate a pathway whereby RGMa cleavage by SKI-1 modifies gene expression related to blood–brain barrier (BBB) integrity after stroke. SKI-1 inhibition restores BBB integrity and neuronal function in mouse and rabbit stroke models.

In this study, the authors assess the global response to the toxic aldehyde glyoxal (GO) in Pseudomonas aeruginosa, suggesting that GO controls quorum sensing during infection through a mechanism involving a novel protein, ArqI.

Aversive and rewarding social experiences are linked to conspecific identity through converging dorsal raphe 5-HT and paraventricular nucleus of the thalamus neurotensin signals in the vCA1 that instruct opposing valence, representing a synaptic switch for flexible social valence computation.

Transferrin receptor (TfR) and CD98hc are increasingly used to enable more effective drug delivery to the central nervous system. Here, the authors reveal comprehensive and distinct brain cellular and whole body biodistribution patterns of TfR- and CD98hc-binding molecules.

Here, the authors show that KDM2A regulates cell cycle progression, modulation of H3K36me2 and H3K27me3 chromatin states and gene repression which are critical for survival of differentiating spermatogonia. KDM2A regulates progression through meiosis as well.

Whether and how hypothalamic neurons can lose or change their identity in adulthood has remained elusive. Here, the authors show that mature pro-opiomelanocortin (Pomc) neurons contain invisible ‘Ghost’ subsets with atypical identities that are recruited in response to obesogenic stimuli.

Brain-wide recordings in mice reveal that prior expectations are distributed through recurrent loops across all levels of cortical and subcortical processing.