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The mechanical stability of proteins affects their import into the nucleus. Now it is shown that protein transport in and out of the nucleus depends on the local mechanostability of the protein cargo.

DNA-sequencing data from primary tumours and paired metastases from participants in the TRACERx lung study and PEACE autopsy programme are used to analyse the metastatic diversity of advanced non-small cell lung cancer and the seeding patterns that underpin it.

Here, the authors elucidate TMPRSS2 protease recognition of the SARS-CoV-2 spike S₂′ cleavage site, revealing the molecular basis of activation of membrane fusion, and show that antibodies recognizing the S₂′ site or TMPRSS2 block viral entry by interfering with TMPRSS2 access.

The rapid evolution of SARS-CoV-2 challenges antibody therapeutics, but glycan-masked antigens enable isolation of class 3 monoclonal antibodies that potently neutralize diverse Omicron variants and reveal cross-reactive epitopes.

The authors resolve 63 structurally diverse haplotype structures for the 22q11.2 deletion syndrome region. Deletion risk differs depending on structure; individuals of African ancestry are enriched for inverted repeats that predispose to inversion.

Immune imprinting narrows the vaccine recall response towards dominant epitopes but protection against rapidly evolving viruses is enhanced if the breadth of responses is preserved. Here authors show in a ferret model that introducing optimized antigenic variation between prime and boost vaccines diversify the targeted epitopes and thus broadens immunity in a ferret model of influenza vaccination.

Kancharla, Kelly et al. identify an acridone antimalarial potent across all major parasite life stages. Lead candidate T111 shows oral efficacy, low toxicity, and synergy with tafenoquine, providing a unique mechanism to overcome resistance.

An analysis of 5,778 domains 28–64 amino acids in length reveals hidden variation in conformational fluctuations, even between sequences sharing the same fold and global folding stability.

Microbiome analysis suggests that gut microbial changes in Parkinson’s disease evolve progressively from healthy individuals to genetically at-risk individuals to clinically affected patients, with the degree of dysbiosis correlating with disease progression.

De novo and inherited dominant variants in genes encoding U4 and U6 small nuclear RNAs are identified in individuals with retinitis pigmentosa. The variants cluster at nucleotide positions distinct from those implicated in neurodevelopmental disorders.

mRNA–lipid-nanoparticle vaccines do not require type 1 conventional dendritic (cDC1) cells or the WDFY4-dependent cross-presentation pathway for CD8⁺ T cell priming but, instead, engage both cDC1 and cDC2 cells redundantly.

The predicted increase in frequency of droughts and rising temperatures in Europe will lead core populations of a temperate plant to an evolutionary dead-end unless they acquire genetic alleles that are present only in extreme edge Mediterranean, Scandinavian, or Siberian populations.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

An in vitro toolkit for studying VSG diversification defines key molecular requirements underlying the formation of mosaic VSGs, providing an experimental framework for the exploration of antigen diversification in Trypanosoma brucei and in other pathogenic microorganisms.

Multi-ancestry and ancestry-stratified genome-wide analyses identify genetic variants associated with refractive error and enable construction of an enhanced polygenic predictor incorporating functional annotations.

Dutta et al. demonstrate that the tumor suppressor complex BRCA1–BARD1 physically interacts with the RNA–DNA helicase Senataxin (SETX) and upregulates the activity of SETX to resolve harmful R-loops crucial for the avoidance of transcription–replication conflicts.

The Nuclear Factor I (NFI) family includes transcription factors key to development, cancer, and genetic disorders. Here, the authors present the structure and DNA-binding properties of NFI-X, a prototype for the entire NFI family.

By combining modelling and simulated data with empirical data from 76 grassland sites across 6 continents, the authors show that the relative abundance of dominant species predicts species richness, while their absolute abundance predicts community biomass.

The taurine–taurine transporter axis is a critical dependency of aggressive myeloid leukaemias.

The low-density lipoprotein receptor family members LRP1, LRP4 and VLDLR are entry receptors for yellow fever virus.

The therapeutic relevance of telomere maintenance mechanisms in cancer, remains to be explored. Here, the authors integrate multi-omic data and functional readouts, generate a resource of telomere biology metrics and identify potential molecular vulnerabilities.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

Single-molecule chromatin fiber sequencing exposes single-cell-level heterogeneity in the chromatin architecture of individual regulatory elements.

It is important to know how the recent COVID-19 pandemic shaped the immune memory against the causal SARS-CoV-2 virus. Here authors show that long years following mild disease at primary infection, SARSCoV-2 spike-specific CD4 + T cells with distinct phenotypes and T cell receptor clonotypes, associated with viral suppression persist.

McGeachan et al. observe oligomeric tau in synapses from individuals with progressive supranuclear palsy and provide evidence that tau pathology may spread through the brain via synapses.

Alterations of therapeutic pressures have been shown to affect clonal evolution of resistance. Here, the authors conducted a single arm, phase 2 trial consisting of alternating osimertinib and gefitinib in non-small cell lung cancer, and found ctDNA dynamics were predictive of response.

Results of an early-phase breast cancer prevention trial demonstrate the potential for breast cancer prevention in premenopausal women with anti-progestin therapy by inducing epithelial–stromal remodelling and suppression of luminal progenitors.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

Trials in rhesus macaques show that a subunit vaccine against SARS-CoV-2, comprising the spike protein receptor-binding domain displayed on a nanoparticle protein scaffold, produces a robust protective response against the virus.

Although DDX41 genetic variation occurs in myelodysplastic syndrome and acute myeloid leukemia, the pathogenic mechanisms remained unclear. Here, the authors found DDX41 regulates CLK3-dependent alternative splicing to establish transcript ensembles, while pathogenic variants limit the activity.

The P2X4 receptor, an ATP-activated ion channel, plays a role in chronic pain, inflammation, and cancer. Authors in this work discover an extracellular allosteric binding site that interacts with anthraquinone derivatives, and is narrowed by ionic lock formation.

Neoadjuvant immunotherapy can induce promising response rates in patients with localised deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) solid tumours but whether this translates to long term survival benefits is less clear. Here, the authors report long-term survival outcomes and ctDNA analysis of a phase II trial investigating neoadjuvant pembrolizumab in patients with dMMR/MSI-H solid tumours.

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).

Environmental influences during prenatal development may have implications for health and disease later in life. Here, Czamara et al. assess DNA methylation in cord blood from new-born under various models including environmental and genetic effects individually and their additive or interaction effects.

Hepatitis C virus (HCV) variability and its phenotypic consequences aren’t well studied in relation to viral replication fitness and disease severity. Here, the authors identify a replication-enhancing domain in non-structural protein 5A, linking high replication fitness to severe disease outcomes, with implications for understanding HCV pathogenesis in immunocompromised patients.

SARS-CoV-2 infection induces long-lived bone marrow plasma cells that correlate with anti-SARS-CoV-2 spike protein antibody titres in individuals who have recovered from COVID-19.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Phenotypic screens in organoids and primary cells are scaled up using perturbation pooling.

CDC25 phosphatases are attractive anticancer drug targets that regulate CDK activity. Here, the authors present the cryo-EM structure of the CDK2-cyclin A-CDC25A complex at 2.7 Å resolution, detailing key protein-protein interactions.

The authors identify a Cys→Ser transformation (C19S) in insulin leading to neoepitope presentation and CD4⁺ T cell autoreactivity in type 1 diabetes. Inflammation and oxidative stress enhanced C19S transformation in β cells and antigen-presenting cells, resulting in C19S-specific CD4⁺ T cells with an activated memory phenotype linked to disease progression.

Unlike squalene, peplusol is only synthesized in a few species of the Euporbia genus and its biosynthetic pathway is unclear. Here, the authors report the discovery and characterization of two peplusol synthases and demonstrate the feasibility of the evolution of peplusol synthase from the ancient squalene synthase.

The SARS-CoV-2 spike glycoprotein is flexible, and its receptor-binding domain (RBD) fluctuates between open and closed conformations. Disulfide bonds are engineered into the spike ectodomain to lock the RBD in the closed state, leading to a construct with high thermostability.

In this study, long-read RNA sequencing achieves accurate single-nucleotide polymorphism calling, haplotype phasing and allele-specific expression analysis.

Convergent mutations in hot spots of the spike proteins of currently circulating SARS-CoV-2 Omicron variants increase the binding affinity for the host receptor and promote more efficient fusion with host cell membranes.

Parity induces an accumulation of CD8⁺ T cells, including cells with a tissue-resident-memory-like phenotype within human normal breast tissue, offering long-term protection against triple-negative breast cancer.

Snyder et al. analyze two population-based birth cohorts to test associations of newborn metabolite concentrations and childhood respiratory outcomes. C4, C10:1, C18:2, and citrulline are associated with early-life wheezing and asthma, with C18:2 specifically associated with increased non-allergic asthma risk.

Kedzierska et al. report an association between low production of receptor-binding domain antibodies after mRNA vaccination and altered glycosylation of IgG before vaccination in people with comorbidities, and show that this condition disproportionately affects Australia’s First Nations peoples because of the high burden of comorbidities in this population.