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Donahue et al. show that ageing is associated with changes in ER morphology. ER-phagy drives age-associated ER remodelling through tissue-specific factors.

Native state proteomics of PV interneurons revealed unique molecular features of high translational and metabolic activity, and enrichment of Alzheimer’s risk genes. Early amyloid pathology exerted unique effects on mitochondria, mTOR signaling and neurotransmission in PV neurons.

Specific pain-sensing nociceptors and chemosensory tuft cells form a circuit to promote type 2 immune responses in the intestine.

Cryogenic electron microscopy structures of human Ostα/β uncover a unique transport pathway featuring two substrate-binding sites connected by an amphipathic helix-gated conduit, and electrophysiological studies demonstrate voltage-sensitive, bidirectional transport, showing its efflux role in vivo.

Bohlen and colleagues report that the E3 ubiquitin ligase CBL is necessary for the development, tolerance and activation of B cells in humans, unlike in mice where CBL deficiency results in loss of T cells.

N¹-Methylpseudouridine enhances the translation of synthetic mRNAs, independently of innate immunity.

Mirusviruses were detected in metagenomic datasets, but little is known about how they infect their hosts. Here, the authors characterize mirusviruses in the marine protist Aurantiochytrium, detecting virions, viral genes and proteins, and establishing this as a valuable model system.

A low-cost robotic platform using mainly optical detection to quantify yields of products and by-products allows the analysis of multidimensional chemical reaction hyperspaces and networks much faster than is possible by human chemists.

Sivanandan, Leitmann, and colleagues present the CellPaint-POSH platform, which combines pooled CRISPR screening with Cell Painting. Using self-supervised deep learning on cell images, the method enables discovery of gene function and biological networks.

Extracellular vesicles (EVs) have shown potential as a therapeutic delivery system for cancer treatment. In here the authors have established HEK293T cells engineered with α-HLA-G VHH antibody-chimeric CD63 protein to promote the production of EVs that can augment the targeting of HLA-G-positive tumor cells

Veiga-Fernandes and colleagues show that neuroepithelial interactions differentially control type 1 and type 2 enteric immunity via VIP–VIPR1 signaling.

This study describes design automation and predictable gene regulatory network engineering in a eukaryotic microorganism.

Extracellular miRNAs are present in a variety of bodily fluids. Here, Freedman et al. analysed plasma-derived RNA by RNA-seq from 40 people followed by targeted RT-qPCR in an additional 2,763 people, and report over 1,000 extracellular RNAs including microRNAs, piwi-interacting RNA and small nucleolar RNAs.

Append editing of ADP-ribosyl to thymine is used for precise modifications in bacteria and eukaryotes.

The impact of tumor intrinsic and immune alterations on disease progression in patients with Waldenstrom’s Macroglobulinemia (WM) remains to be characterized. Here, the authors perform single-cell RNA-sequencing and identify distinct tumor subtypes, tumour microenvironment features and potential therapeutic vulnerabilities in patients with WM.

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.

The bacterial ubiquitin ligase NleL evades host defence mechanisms both by inhibiting pyroptosis and by preventing infected intestinal epithelial cells from being extruded into the lumen and expelled in the faeces.

In this work, through a comprehensive proteomics approach, the authors identified host plasma protein biosignatures that could distinguish tuberculosis (TB) disease in children.

Jee et al. study a cancer hotspot allele of DICER1 that disrupts RNaseIIIb activity. Beyond ablating 5p hairpin cleavage, 3p passenger strands are globally upregulated and active. Thus, this setting induces both loss and gain of miRNA function.

Single-cell proteomics is an emerging approach to characterize cell-to-cell differences. Here, the authors develop chips that enable complete proteomic sample processing down to the single-cell level and integrate them with DIA-MS into a streamlined single-cell proteomics workflow.

Pathology-oriented multiplexing (PathoPlex) represents a framework for widespread access to multiplexed imaging and computational image analysis of clinical specimens at a relatively high throughput and subcellular resolution.

A newly identified gene, sex chromosome activation (SOA), is a master regulator of dosage compensation in Anopheles gambiae.

Here authors used patient-derived forebrain organoids to reveal how LIS1 mutations cause varying severity in a neurodevelopmental disorder, uncovering links between cytoskeletal defects, protein stress, and potential therapeutic strategies.

The small molecule GS-6207, which disrupts the function of the HIV capsid protein, shows potential as a long-acting therapeutic agent for the treatment and prevention of HIV infection.

Kim and coworkers describe a technique, EPSILON, to map AMPA receptor exocytosis, a proxy for synaptic plasticity, in mice. The authors demonstrated a correlation between AMPA receptor exocytosis and cFos expression during a fear conditioning experiment.

Attenuating effects of the ketogenic diet on colorectal cancer (CRC) cell growth has been previously described. Here, using a mouse model of CRC with a humanized microbiome, the authors identify a shift toward gut bacterial species that produce stearic acid in ketogenic conditions, resulting in elevated levels of free stearate in the gut lumen, which they then show exhibits tumor-suppressing properties.

LRP8, an apolipoprotein E and reelin receptor with high expression in the brain, is a receptor for tick-borne encephalitis virus.

Human airway contains physiologically relevant yet rare cells, but their scarcity prevents thorough profiling and differentiation studies. Here the authors use single cell RNA sequencing to identify rare ionocytes and tuft cells, as well as a potential progenitor population with cytokine-guided differentiation into either the ionocytes or tuft cell lineage.

Reductive aminases show strong potential for the sustainable synthesis of chiral amines, but their application in industrial scale processes is lacking. Now, such an enzyme is screened and engineered allowing its use in commercial manufacturing of abrocitinib JAK1 inhibitor in multi-metric tons.

Depletion of a transcriptional factor ZBTB11 using molecular glue degraders can overcome oxidative-phosphorylation-mediated KRAS inhibitor resistance in pancreatic ductal adenocarcinoma with low acute neurotoxicity.

Anandasabapathy and colleagues show that the inhibitory receptor PD-1 impacts the specification of tissue-resident memory T cells in the skin.

Self-assembled multidomain supramolecular peptide hydrogels that engage in dynamic covalent bonding with small-molecule drugs and biologics are shown to offer sustained release, extend the activity, and maintain safe and potent drug levels in vivo.

The majority of excitatory neurotransmission in the central nervous system is mediated by ionotropic glutamate receptors, which function by opening a transmembrane ion channel upon binding of glutamate. However, despite this crucial role in neurobiology, the architecture and atomic structure of an intact isotropic glutamate receptor are unknown. The X-ray crystal structure of the rat GluA2 receptor in complex with a competitive antagonist is now reported and analysed.

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.

Mechanisms underlying sleep dysfunctions in neurodevelopmental disorders remain elusive. Here, authors use a fly model for the CYFIP haploinsufficiency to show that increased SREBP activity impairs the NADP+/NADPH homeostasis inducing sleep deficits.

This study showed that vagal sensory neurons in the nodose ganglia selectively encode specific cytokines, enabling real-time body-brain communication of immune signals. This neural encoding of cytokines is disrupted during inflammation associated with a colitis model.

T follicular helper cells (Tfh) enhance antibody responses and can circulate or be resident in lymph nodes. Here the authors show that during acute SARS-CoV-2 infection, circulating Tfh cells correlate with antibody titres and plasmablast levels but in more severe COVID-19 cases, cTfh generation is delayed.

Microglia-derived IGF1 promotes the proliferation of GABAergic progenitors and neuroblasts in the human medial ganglionic eminence, contributing to the extended production of GABAergic neurons and an expanded cognitive capacity in the human brain.

SLC25A39 and its paralogue SLC25A40 have redundant roles in the import of glutathione into mitochondria of mammalian cells.

This paper shows that compulsive-like grooming in Sapap3-knockout mice can be reduced by closed-loop optogenetic stimulation of striatal interneurons based on grooming onset prediction, suggesting that adaptive stimulation may have therapeutic potential in obsessive–compulsive disorder.

A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

Single-stranded DNA annealing is driven by RAD52 open rings in association with RPA.

Expression of VIM-2 leads to physiological trade-offs for bacterial pathogens that can be exploited to treat infections caused by multidrug-resistant bacteria.

A small-molecule inhibitor of TMPRSS2 is effective against SARS-CoV-2 variants of concern in human lung cells and in donor-derived colonoids, and also shows prophylactic and therapeutic benefits in a mouse model of COVID-19.

Plasma P-tau18 level increased with progression of Alzheimer’s disease (AD) and differentiated AD dementia from other neurodegenerative diseases, supporting its further development as a blood-based biomarker for AD.

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.