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Robust bioanalytical and modeling methods are needed for covalent drug discovery. Here, the authors demonstrate a mass spectrometry (MS) assay to measure target engagement of any drug-target protein complex, a universal PK/PD model for covalent drugs, and a decision tree to guide research.

Polygenic risk scores can help identify individuals at higher risk of type 2 diabetes. Here, the authors characterise a multi-ancestry score across nearly 900,000 people, showing that its predictive value depends on demographic and clinical context and extends to related traits and complications.

Plasma proteomics plays a key role in advancing clinical research and biomarker discovery. Here, the authors show in a large MSCoreSys multicenter benchmark study that DIA outperforms DDA, delivering robust, precise, and reproducible label-free protein quantification across sites.

An extinct prehistoric plague lineage of Yersinia pestis has been documented from Central Europe to Asia during the Late Neolithic and Bronze Age. Here, Swali et al. show that this lineage spread to Europe’s northwestern periphery by sequencing three ~4000 year-old Yersinia pestis genomes from Britain.

Crohn’s disease is associated with altered intestinal microbiota. Here, the authors show that the microbe Atopobium parvulumis associated with Crohn’s disease patients, triggers colitis in a mouse model, and that scavenging microbe-induced hydrogen sulfide improved symptoms in mice.

A study describes an approach using designed building blocks that are far more regular in geometry than natural proteins to construct modular multicomponent protein assemblies.

Understanding the underlying pathophysiology of obesity can help prevent this condition. Here, the authors perform a GWAS of BMI in diverse ancestries, finding four missense variants in FRS3 that affect BMI.

Adoptive T-cell immunotherapy offers promise to patients who are resistant to standard anti-viral strategies. Here the authors describe clinical observations in patients with viral complications treated with adoptive immunotherapy over the last 15 years.

Studies using mouse models of lung adenocarcinoma identify an association between age, iron homeostasis and tumour initiation potential that involves NUPR1 and lipocalin-2.

Non-neutralizing antibodies against the nucleoprotein (NP) of Crimean-Congo hemorrhagic fever virus are protective against lethal challenge in mice. Here, the authors show that these anti-NP antibodies protect through the intracellular antibody receptor TRIM21 and that protection is independent of T cells.

Findings on solar activity in the first millennium CE confirm four Grand Solar Minima and indicate two patterns of weakening-then-strengthening in the Schwabe cycle, providing insights into solar dynamo behavior, according to analysis of Δ14C data from tree rings.

Lowering the levels of coagulation factor XII may prevent thrombosis without increasing the risk of bleeding. Here, Haj et al. use a large human dataset to show that this is the case for people carrying mutations that lower the levels of factor XII.

Venniro et al. report that drug-addicted rats reliably choose contact with another rat over drugs, even when group-housed between tests. They also do not show the increase in drug craving that normally occurs during forced abstinence.

The pandemic of COVID-19, caused by SARS-CoV-2 infection, warrants immediate investigation for therapy options. Here the authors show, using epithelial and air-liquid interface cultures, that SARS-CoV-2 hijacks host cell metabolism to facilitate viral replication, and that inhibition of mTORC1, a master metabolic regulator, suppresses viral replication.

Tacto et al. uncover a key marker that enables the selection of functional, transplantable human islets derived from stem cells, potentially paving the way for more precise and effective diabetes cell therapy.

Here, the authors generate a replication-competent VSV based vaccine expressing SARS-CoV-2 spike protein and show protection in the hamster model with one dose. Analysis of the antibody response in mice shows induction of neutralizing antibodies and suggests a desirable Th1-biased response to the vaccine.

CMOS-based circuits can be integrated with silicon-based spin qubits and can be controlled at milli-kelvin temperatures, which can potentially help scale up these systems.

The integration of liver and plasma quantitative lipidomic and proteomic data from 107 distinct mouse strains provides important insights into regulators of mammalian lipid metabolism.

Study of human heart failure is limited by access to human tissue. Here, the authors apply multi-omic screening in human ischaemic and dilated myocardial tissue and matched controls to determine molecular changes common and unique to each aetiology and to reveal differences between male and female hearts.

How higher-order thalamic feedback modulates sensory-evoked cortical activity is not fully understood. This study reveals that synaptic feedback from the thalamus selectively increases the excitability of distinct cortical neurons through NMDARs and mGluR-mediated modulation of potassium channels, thereby enhancing sensory processing.

The neoantigen discovery pipeline NeoDisc incorporates mass spectrometry immunopeptidomics data.

Native ion mobility mass spectrometry reveals two isoforms of the two-pore domain K⁺ channel K2P4.1 have distinct binding preferences for lipids and show a relationship between the strength of individual lipid binding events and channel activity.

In lung adenocarcinoma, antibodies against endogenous retroviruses promote anti-tumour activity, and expression of endogenous retroviruses can predict outcomes of immunotherapy.

Using a unique and rich data set of lifetime cognitive measures, the contribution of genetics to differences in cognitive ageing is explored.

Sequencing studies in clinical and cancer genomics often utilize public data sets to identify genes enriched with pathogenic variants. Here, the authors propose a framework which controls for confounding factors that can bias the results in these studies.

Capsule-specific human monoclonal antibodies are protective against bloodstream infection by Klebsiella pneumoniae sequence type 147 in a mouse model of septicaemia, and could provide a useful strategy against pathogens with antimicrobial resistance.

The treatment potential of psilocybin for postpartum depression was investigated in a preclinical mouse model. Here the authors show both acute and long-term effects of psilocybin in mothers and their offspring who were exposed via lactation.

Despite a rise in COVID-19 cases among children, there is limited understanding of the antibody responses mounted, compared to in adults. In this work, authors compare seroconversion rates and antibody responses in unvaccinated Australian children across the three SARS-CoV-2 waves (Wuhan, Delta and Omicron).

Aging drives distinct molecular changes in the brain. Here, the authors use scRNAseq and MERFISH and find that in mice, aging induces subtype-specific, regionally biased changes in striatal astrocytes, marked by transcriptional repression, inflammation, and impaired neuronal interactions.

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.

The role of IgG glycosylation in the immune response has been studied, but less is known about IgM glycosylation. Here the authors characterize glycosylation of SARS-CoV-2 spike specific IgM and show that it correlates with COVID-19 severity and affects complement deposition.

The function of the lymphocyte-expressed receptor CD96 is almost entirely unknown. Smyth and colleagues demonstrate that it serves a key role in restraining activation of NK cells in part by competing with the activating receptor CD226 (DNAM-1).

A single-cell ex vivo screening of repurposable drugs in glioblastoma and machine learning of drug–target networks show that anti-tumor neuroactive drugs converge on the AP-1/BTG pathway, based on which prediction models and experimental in vivo and in silico validation identify the anti-depressant vortioxetine as a potential therapeutic agent.

The majority of human genes can produce multiple isoforms, but studying their functional relevance requires tools to target specific isoforms. Here, the authors develop a CRISPR-based exon-exon junction-targeting strategy to achieve isoform-specific RNA knockdown.

scRNAseq analysis of human lung T cells complemented with clinical data provides new mechanistic insights into the pathophysiological role of adaptive immune cells in emphysema.

FIKK effector kinases underwent rapid evolutionary expansion and are a druggable target in Plasmodium falciparum.

Afforestation is an important greenhouse gas (GHG) mitigation strategy but the efficacy of commercial (harvested) forestry is disputed. Here the authors apply dynamic life cycle assessment to show that new commercial conifer forests can achieve up to 269% more GHG mitigation than semi-natural forests, over 100 years.

Results from the randomized ProfiLER-02 trial, which compared two gene panels in guiding molecular-based treatment in patients with solid tumors, show that a broader gene panel led to more molecular-based recommended therapies compared to a more limited gene panel.

A standardized, realistic phantom dataset consisting of ground-truth annotations for six diverse molecular species is provided as a community resource for cryo-electron-tomography algorithm benchmarking.

Licheva, Pflaum, Babic, Mancilla et al. show that low-affinity cargo–receptor interactions promote autophagy receptor mobility and condensation of the scaffold protein Atg11 to trigger initiation hub and phagophore formation.

A novel antiviral targeting the SARS-CoV-2 PLpro protease shows strong efficacy in a mouse model, preventing lung pathology and reducing brain dysfunction. The study provides proof-of-principle that PLpro inhibition may be a viable strategy for preventing and treating long COVID.

The field of cellular agriculture has relied on 3D bioprinting for the generation of sophisticated products. Here, the authors employ chaotic bioprinting to create plant and animal cell-based hybrid noodles, thereby opening avenues to produce complex culinary designs and to explore diverse nutritional alternatives.

The distribution and organisation of matrix molecules in the tumour stroma help shape solid tumour progression. Here they perform temporal proteomic profiling of the matrisome during breast cancer progression and show that collagen XII secreted from CAFs provides a pro-invasive microenvironment.

Chemical proteomics profiling of 1,183 kinase inhibitors from past drug discovery projects revealed a large number of reasonably selective compounds for several kinases such as SYK and CK2.