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González-Gualda, Reinius et al. demonstrate that platinum-based chemotherapy-induced senescence promotes malignancy in ovarian and lung cancer via TGFβ ligands, with evidence in mouse models validated in clinical samples. Concomitantly blocking TGFβ signaling with chemotherapy reduces tumor burden and increases survival in mice.

Mechanical forces play a crucial role during morphogenesis, but how these are sensed and transduced in vivo is not fully understood. Here the authors apply a FRET tension sensor to live zebrafish and study changes in VE-cadherin tension at endothelial cell-cell junctions during arterial maturation.

Stalling of ribosomes by the nascent polypeptide chain is widely used to regulate gene expression. Here, Gersteuer et al determine cryo-EM structures of SecM-stalled ribosomes revealing the mechanism by which the SecM peptide arrests translation.

Scaling Si spin qubits relies on the uniform control of qubit-host interactions. This work finds correlations in qubit energy levels across a manufactured device arising from placement of Ge in the quantum well, consistent with atomistic modeling.

Dinoflagellates and cyanobacteria produce saxitoxin (STX) congeners that block voltage-gated sodium channels. Here authors show how amphibians may sequester STX congeners using a ‘lock and key’ mode, expanding the understanding of toxic sponge action.

Pfs25 is a transmission-blocking vaccine candidate for Plasmodium. Here, McLeod et al. analyze the antibody response to Pfs25 in sera from a clinical trial evaluating a Pfs25 vaccine candidate, identify a potent transmission-blocking antibody and determine recognized epitopes on Pfs25.

Koller et al. determined structures of the O-glycosylated antimicrobial peptide drosocin from Drosophila melanogaster in complex with the bacterial ribosome, revealing the mechanism by which drosocin inhibits the termination phase of protein synthesis.

Taveneau et al. leverage artificial-intelligence-driven protein design to create inhibitors that control RNA-targeting enzymes in cells, revealing a strategy to rapidly design off-switches for RNA-editing systems.

In one-shot perceptual learning, what we see can be dramatically altered by a single past experience. Using psychophysics, fMRI, iEEG, and DNNs, the authors identify neural and computational mechanisms underlying this remarkable ability in humans.

DNA recognition and cleavage control in type II topoisomerases are poorly understood processes. Here, the authors determine cleaved and uncleaved structures of supercoiled DNA-bound topoisomerase VI that reveal how the enzyme activates its cleavage state and prefers to act at deformable substrates.

In mice, DHPS supports the maturation, maintenance and function of tissue-resident macrophages via the polyamine–hypusine axis, with implications for macrophage-targeting therapies.

KRAS mutations are keenly associated with pancreatic ductal adenocarcinoma and represent a potential therapeutic target. Here the authors present the findings from a phase I clinical trial testing pooled KRAS mutant peptides in combination with immune checkpoint blockade in patients with resected pancreatic ductal adenocarcinoma.

The authors report the structural basis of site-one protease (S1P) activation by SREBP regulating gene (SPRING). They show that SPRING displaces the inhibitory pro-domain of S1P, enabling S1P to cleave its canonical substrate SREBP2.

Current models suggest that DLK1 is an inhibitory ligand in the Notch pathway. Here, the authors show that DLK1 does not interact with Notch receptors, instead blocking Activin signaling via an interaction with Activin receptor type-2B.

Roy-Chowdhury et al. report structures of the human leak channel K_2P13.1 that identify a hydrophilic pore restriction and a polyunsaturated-fatty-acid-binding site corresponding to a small-molecule agonist site in the K_2P family.

Results of the phase 2 POLAR trial show that biomarker-guided treatment in patients with metastatic pancreatic cancer based on homologous repair deficiency leads to encouraging clinical response rates in immune cell-infiltrated tumors.

Massively parallel reporter assays across five cell types identify thousands of causal, noncoding regulatory variants among 220,000 loci, revealing diverse regulatory mechanisms shaping complex traits and disease.

Analysis of snRNA genes in individuals with rare disorders identifies de novo and recurrent variants in RNU5B-1 and RNU5A-1, in addition to previously unreported cases with pathogenic or likely pathogenic variants in RNU4-2.

Here, the authors examine the mechanisms behind cheatgrass’s successful invasion of North American ecosystems. Their genetic analyses and common garden experiments demonstrate that multiple introductions and migrations facilitated cheatgrass local adaptation.

Plant traits drive ecosystem dynamics yet are challenging to map globally due to sparse measurements. Here, the authors combine crowdsourced biodiversity observations with Earth observation data to accurately map 31 plant traits at 1 km² resolution.

The non-coding RNA RNU4-2, which is highly expressed in the developing human brain, is identified as a syndromic neurodevelopmental disorder gene, and, using RNA sequencing, 5′ splice-site use is shown to be systematically disrupted in individuals with RNU4-2 variants.

Polyketide macrolides are of interest for drug discovery but their inherent structural and stereochemical complexity hinders the exploration of related regions of chemical space more broadly. Here, the authors designed in silico and synthesized a library of tetrahydrofuran-containing polyketide macrolides, and screened them against a panel of biological assays, identifying biologically active library members.

Trypanosoma brucei, which is responsible for human sleeping sickness, has an intrinsic circadian clock that regulates metabolism and influences drug sensitivity.

Chimeric particles are formed when influenza A virus and respiratory syncytial virus coinfect lung cells in vitro.

In this study, authors employ fragment-based lead discovery to identify WRN inhibitors. The fragment hits reveal an additional allosteric pocket and uncover a previously uncharacterized structural conformation of the WRN helicase domain with unique orientations of the ATPase domains

Eosinophils enhance granuloma-mediated control of persistent Salmonella infection in mice through CCL11-driven recruitment and MBP-dependent modulation of macrophage polarization and bacterial clearance.

mRNA medicines hold enormous promise for drugging targets outside the reach of classic small molecules. Here, the authors develop a modular platform to design programmable mRNA therapeutics that act by modifying epigenetic state.

CaBLAM is a bioluminescent genetically encoded calcium indicator that delivers high-contrast signals as shown in cell culture, in the in vivo mouse brain and in zebrafish larvae.

Computational methods are becoming an increasingly important part of biological research. Using the Rosetta framework as an example, the authors demonstrate how community-driven development of computational methods can be done in a reproducible and reliable fashion.

The authors report a 2.6 Å resolution crystal structure of the human CB1 cannabinoid receptor trapped in the inactive conformation and bound to the antagonist taranabant.

Previous theoretical interpretations of the Rydberg spectra of dimethylpiperazine (DMP) debated the existence of a localized minimum on the surface of the DMP+ cation. Here, the authors show a substantial influence of the Rydberg electron on the molecular structure, restoring the localized minimum.

Monitoring samples from hospital patients, wastewater, or air travel may enable early detection of pathogens. Here, the authors assess how these surveillance systems could have impacted detection of COVID-19 and their potential benefits for detection of other emerging pathogens.

Here the authors establish somatic loss-of-heterozygosity as a genetic underpinning of Cerebral Cavernous Malformations (CCMs): using single-nucleus DNA sequencing, they show homozygosity of chromosomes 7p and/or 7q leads to biallelic inactivation of CCM genes in resected lesions.

Coordinated proliferation and differentiation of diverse cell populations drive pancreatic epithelial and mesenchymal development. Here, the authors profile cell type dynamics in the developing mouse pancreas using single-cell RNA sequencing, identifying mesenchymal subtypes and undescribed endocrine progenitors.

Varicella-zoster virus (VZV) establishes lifelong neuronal latency in humans. Here, Ouwendijk and Depledge et al. identify a fusion transcript, VLT-ORF63, which is expressed during lytic and latent infection, and demonstrate a role for the translated fusion protein in induction of lytic gene expression from latent VZV genomes.

Nitric oxide (NO) is a potent vascular signaling agent, but its bioavailability is limited through rapid scavenging reactions. DeMartino et al. characterize the formation and bioactivity of NO-ferroheme, a stable NO analog that forms readily, bypasses scavenging reactions and mediates NO signaling.

Phage capsids modified with spatially defined patterns of host cell ligands can act as multivalent binders for the influenza A virus to prevent viral infection.

Rechtzigel et al. perform a comprehensive multi-omics study using serum from CLN3Δex7-8 minipigs, identifying blood-based molecular changes linked to disease progression. These data are used to create a biomarker scoring framework accurately distinguishing healthy from affected pigs.

Engineered gene circuits often degrade over time due to mutation and selection. Here the authors use a host-aware modelling framework to develop genetic controllers to sustain synthetic gene expression. They identify a range of design trade-offs in production, robustness and long-term performance.

Despite not conserved in all mammals, TRIM52 is crucial for fitness in human cells. Here, the authors show that TRIM52 interacts with the DNA repair machinery to prevent cell-cycle arrest, and that TRIM52 is rapidly degraded by multiple giant E3 ligases. These findings link TRIM52 to genome integrity control.

The bifunctional enzyme CoaBC catalyses the second and third step in the Coenzyme A (CoA) biosynthesis pathway and is of interest as a M. tuberculosis drug target. Here, the authors present the full-length crystal structure of Mycobacterium smegmatis CoaBC, which is regulated by CoA and CoA thioesters and forms a dodecamer and by performing a high-throughput screen they identify selective inhibitors of M. tuberculosis CoaB that bind to an allosteric site within CoaB.

McGavern and colleagues identified a CD8⁺ T cell population that expresses GZMK in ʽtau-richʼ brains, where it may play a protective role against neurodegeneration.

Determining structures of small, protein-free RNAs by cryo-EM has been challenging. Here, the authors use a group II intron scaffold to achieve high-resolution RNA structures, visualize ligand-induced changes, and enable de novo modeling of non-coding RNAs.

In bacteria, the ribosomal stalling during translation of leader peptides is a mechanism of antibiotic resistance that has not been well understood. Here, the structure of a drug-dependent stalled ribosome complex has allowed the authors to propose a detailed mechanism for this translational arrest.

Zymoseptoria tritici is an important fungal pathogen of wheat which has spread globally. Here, the authors perform genomic analyses on a collection of ~1100 Z. tritici samples from 42 countries to describe its global spread and elucidate mechanisms of adaptation to different environmental conditions.

The authors report crystallographic and computational studies that detail how SARS-CoV-2 3CLpro cleaves the host NF-κB Essential Modulator in addition to its canonical viral substrates. The association with the high fitness of SARS-CoV-2 in humans is discussed.

Biological and artificial systems encode information through complex nonlinear operations across multiple timescales. In multiscale information-processing systems, this study examines and compares the performance of nonlinear integration, where signals are combined before transformation, to nonlinear summation, where signals are transformed before combination, and offers insights into features governing nonlinear signal processing.