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Rhine et al. find that neuronal aging leads to widespread dysregulation of RNA biology, including mislocalization of splicing proteins like TDP-43, chronic cellular stress and reduced resiliency.

Analysis of a placebo-controlled trial of a BCMA-targeting CAR-T cell therapy in patients with myasthenia gravis shows that CAR-T cell infusion selectively remodels the systemic immune environment, with elimination of BCMA-high plasma cells and activated plasmacytoid dendritic cells and changes in the autoreactive B cell repertoire.

Here, the authors show that pharmacological and genetic mineralocorticoid receptor antagonism reduces intestinal fibrosis in mice and that NGAL is involved in mineralocorticoid receptor-mediated intestinal fibrogenesis.

A gene therapy method using AAV can help deliver HIV-fighting antibodies long-term, but the body often rejects them. Here the authors show that a short course of the drug rapamycin helps prevent host anti-drug antibody responses, showing successful antibody delivery in mice and monkeys.

Seegren et al. demonstrate that the mitochondrial calcium uptake complex is a key molecular apparatus that links age-related changes in mitochondrial physiology to systemic macrophage-mediated age-associated inflammation.

Regulation of tissue growth is crucial for development, but the underlying mechanisms remain unclear. Here, the authors identify a role for deubiquitylating enzymes in the regulation of the function of the atypical cadherin Fat and Hippo signalling.

DNA hydroxymethylation (5hmC) is typically altered in age-related diseases. Here, the authors show that 5hmC accumulates in gene bodies, partially due to prolonged quiescence, and restricts the magnitude of transcriptional changes with age.

Recently published results from a Phase I trial showed the blood brain barrier could be transiently opened in glioblastoma patients using low-intensity ultrasound and microbubbles. Here, the authors develop a microfluidic chip to capture tumour-derived extracellular vesicles and particles in response to paclitaxel treatment.

Using visible-light-induced crosslinking, a local stiffening approach is developed for ex vivo mouse and human lung tissue as an early lung injury model, directing epithelial cell mechanosensing, differentiation and nascent protein deposition.

Myelin regeneration can occur spontaneously in demyelinating diseases but the underlying mechanisms are incompletely understood. Here the authors show that neuronal activity and glutamatergic synapses instruct oligodendrocyte progenitor cells to differentiate into new myelinating oligodendrocytes.

Ramabadran et al. identify a DNA methylation-independent role for DNMT3A in stem cell activation, mediated through recruitment of SF3B1 and splicing regulation.

Positron emission tomography measurements of nutrient uptake in cells of the tumour microenvironment reveal cell-intrinsic partitioning in which glucose uptake is higher in myeloid cells, whereas glutamine is preferentially acquired by cancer cells.

Here the authors reveal how an incoherent feedforward C/EBPα–Notch circuit times lung cell fate, guiding alveolar development, repair after injury, and shifts between protective and reparative states.

Jin et al. discovered Atlantic grey seal milk contains 332 complex sugars, including 166 novel structures. Seal milk rivals human milk complexity, includes giant molecules up to 28 sugar units, changes during lactation, and shows immune-boosting effects.

Metabolite extraction with organic solvents is assumed to remove/denature proteins. Here, the authors uncover a vast landscape of >1,000 proteins in metabolite extracts. These proteins can retain catalytic activity and drive post-extraction metabolite changes, obscuring biological interpretation.

Here the authors identify adenophages, a previously unknown macrophage population present in exocrine glands in mice and humans. These cells are dependent on ILC2-derived GM-CSF and support glandular homeostasis.

C9orf72 ALS/FTD polyGR and polyPR knock-in mice show cortical hyperexcitability and motor neuron loss accompanied by an increase in extracellular matrix proteins in the spinal cord that is conserved in patient iPS cell-derived neurons and is neuroprotective.

SARS-CoV-2 infection is milder in children, but direct comparison with adults is rare. Here the authors show that immune responses are higher in children, retained for 12 months or longer and can neutralize Alpha, Beta and Delta variants.

This study maps the connections of layer 5 pyramidal neurons in the mouse cortex, revealing distinct local and intercortical wiring patterns, and provides an open framework for exploring the connectivity of cell types.

Insight into the algorithmic form and learning principles underlying cognitive maps in the hippocampus is provided.

Cells spatially organize biochemical reactions within membrane-bound and membraneless compartments. The extent to which intrinsically disordered proteins themselves can form discrete compartments or condensed phases is poorly understood. Now a pair of model IDRs that display orthogonality in condensation and the chain features governing selective assembly have been identified.

Chen et al. show that in mice, extracellular matrix remodeling drives early migration of the anterior signaling center, establishing the body axis sooner than expected—a mechanism potentially conserved in humans.

This study investigates the effects of MYCN on the chromatin and transcriptional landscape of neuroblastoma. The authors find that, at oncogenic levels, MYCN binds to canonical E-boxes at promoters and invades enhancers, leading to transcriptional amplification.

Branched chain ketoacid dehydrogenase kinase (BDK) inhibits the activity of branched chain ketoacid dehydrogenase and branched chain amino acid degradation, implicated in several diseases. Here, the authors discover a BDK inhibitor and degrader that shows efficacy in rodent metabolism and heart failure models, as well as another class of BDK inhibitors that stabilizes BDK.

Individuals with malignant hyperthermia susceptibility (MHS) suffer from lifethreatening responses to heat. Here the authors demonstrate that adaptive thermogenesis from brown adipose tissue contributes to this heat sensitivity in a preclinical mouse model of MHS

Mazan-Mamczarz, Tsitsipatis and colleagues apply single-cell and spatial transcriptomics to mouse models of atherosclerosis to map senescent cells contributing to plaque instability and arterial remodeling. They define a transcriptomic signature of vascular senescence.

Giafaglione et al. define metabolic regulation of prostate epithelial lineage identity and show that modulation of lactate metabolism alters response to antiandrogen therapy.

De novo assemblies of 43 Y chromosomes spanning 182,900 years of human evolution reveal considerable diversity in the size and structure of the human Y chromosome.

UCHL5 is a deubiquitinating enzyme that cleaves Lys-48-linked polyubiquitin chains. Here, the authors discover through in-vivo CRISPR-Cas9 screens that Uchl5 is involved in immune evasion and modulation of extracellular matrix deposition in head and neck squamous cell carcinoma.

Rheumatoid arthritis is an inflammatory disease that selectively affects different joints. Here the authors show that gene expression and DNA methylation patterns of fibroblast-like synoviocytes differ between hip and knee joints in patients with RA, thus providing epigenetic and transcriptomic evidence for this anatomic selectivity of inflammation.

Glycomic profiling of mucosal surfaces identified O-mucin glycoconjugate motifs that regulate Candida albicans virulence. Synthetic analogs based on these glycans suppress fungal filamentation, offering potential for antifungal development.

Primary angle-closure glaucoma is a leading cause of blindness. Here, the authors identify rare deleterious variants in UBOX5 as risk factors and implicate BIP ubiquitination as a potential disease mechanism.

Systemic lupus erythematosus (SLE) is associated with altered B cell responses but the underlying aetiology is still unclear. Here the authors show that a CD11c^hiT-bet⁺ B cell subset with a unique phenotype and transcriptome is increased in patients with SLE, can be expanded by IL-21, and may contribute to autoimmune responses in SLE.

Erlich et al. show that soluble LTα and membrane-bound LTα1β2 lymphotoxins expressed by B cells play distinct roles to attenuate the pathology observed in ileitis.

Thousands of recombinant antibodies enriched for specificity against defined targets are assembled in multivalent mixtures with enhanced therapeutic activity.

Messenger RNAs transcribed from olfactory-receptor genes may have non-coding functions that include recruitment of transcriptional enhancers and inhibition of potentially thousands of competing alleles to ensure stable transcription of a single allele.

Using single-molecule super-resolution microscopy, researchers revealed that Tau controls the recycling pool of synaptic vesicles in hippocampal neurons by forming nanoscale biomolecular condensates that are dynamically regulated by neuronal activity.

The small cell size of bacteria is a key hurdle in studying condensates. To address this challenge, the authors develop an experimental framework to assess bacterial condensates based on how they form, dissolve, tune shape and size, and transition between material states.

Glioblastoma—the deadliest form of brain cancer—alters the calvarial bone and its marrow components, pushing it toward producing more myeloid cells and contributing to an immunosuppressive environment.

In Alzheimer’s disease (AD), disruptions in myelin and axonal structures occur, although the underlying mechanisms remain unclear. Here the authors show that, at the myelin–axon interface, axon–glial signaling, paranodal architecture and amyloid-β aggregation are altered in AD, implicating myelin–axon disruption in disease progression.

Current first-line treatments of pediatric UC maintain a 6-month remission in only half of the patients. Here, applying multi-omics on intestinal biopsies from treatment-naïve children, the authors show that relapse-prediction using separate omics data is outperformed by a robust machine learning approach combining microbiomes and epigenomes.

Studies on the essentiality of Ku in human cells reveal that Ku interacts with diverse double-stranded RNA molecules, including antisense Alu, and enables tolerance of Alu sequence expansion in primates.

An analysis of skeletal stem cells in mice reveals that bone ageing occurs at the level of local niches affecting skeletal and haematopoietic lineage output, which may influence systemic aspects of multi-organ physiological ageing.

Vaccination efficiency in HIV infection is hampered by the low immunogenicity of HIV-1 Env glycoprotein (Env). Here authors optimise the neutralising antibody response to Env by stabilizing the Env trimers in the context of expressing them in a Newcastle Disease Virus-like particle and providing conditions that mimics replicating virus infection.

Compartments of neurons can sometimes act as independent computational units. Here the authors show that retinal bipolar cells, some of the smallest mammalian neurons, send different signals to downstream ganglion cells via different synapses.

Zhu et al. discover that in human brain there is widespread anatomic distribution of low-frequency somatic, mosaic L1 insertions, using deep whole-genome sequencing of neuronal and glial fractions and machine-learning analysis.

Dietary serine and glycine starvation has emerged as a potential therapy for cancer. Here, the authors show that inhibition of PHGDH, which mediates the first step in the serine synthesis pathway, improves the therapeutic efficacy of serine depletion diet in mouse xenograft models.

Here, the authors show that the Hox genes Antennapedia (Antp) and Ultrabithorax (Ubx) control flight appendage morphology in Drosophila. This role is dependent on a particular spatial expression profile and dosage, which was also found in evolutionary distant four-winged insect species.