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The structure and biological properties of RNAs are a function of changing cellular conditions. Here, Baird et al.report a high-throughput Förster resonance energy transfer (FRET) method to rapidly compare RNA structure modulation by cognate and non-cognate ligands across multiplexed solution conditions.

Genome-wide analyses identify 30 independent loci associated with obsessive–compulsive disorder, highlighting genetic overlap with other psychiatric disorders and implicating putative effector genes and cell types contributing to its etiology.

The RNA for ALS- and frontotemporal dementia-associated C9ORF72 gene is exported from nucleus via an unknown mechanism. This study shows that reduction of nuclear export adaptor SRSF1 can alleviate neuronal cell death and nuclear export of C9ORF72 inDrosophilaand patient-derived induced motor neurons.

The enzyme ABHD18 is shown to have a key role in cardiolipin metabolism in mitochondria, offering a potential route for a small-molecule treatment of the rare genetic disease Barth syndrome.

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.

The beta variant (B.1.351) is to date the most resistant to neutralization of the SARS-CoV-2 variants. Using nonhuman primates, Seder and colleagues demonstrate that double vaccination with a high dose of the lipid nanoparticle vaccine mRNA-1273 protects against infection with the beta variant.

Food protein amyloid fibrils have superior properties but due to safety concerns, have not yet been used in foods. In-vitro and in-vivo studies here show that upon digestion they are safe and can be used as potential ingredients for human nutrition.

Alterations in the tumour suppressor genes STK11 and/or KEAP1 can identify patients with advanced non-small-cell lung cancer who are likely to benefit from combinations of PD-(L)1 and CTLA4 immune checkpoint inhibitors added to chemotherapy.

Immunotherapy is at an inflection point. After three decades of accelerating progress, immunotherapy is entering the realm of in vivo engineering. This Comment discusses the potential of in vivo engineering in addressing challenges met by ex vivo engineering efforts. Per a recent workshop organized by the National Institutes of Health, we highlight progress, the platform technologies fueling it, and elements of a road map and challenges ahead.

By individually replacing 16 yeast genes encoding ABC transporters by GFP, mating and selecting for strains with accumulated mutations the authors create a Green Monster, a strain with deletions in all 16 genes.

Sulphur isotopes track recycling of subducted crustal material, yet few igneous rocks preserve these signals over Earth history. Here, the authors investigate a billion-year-old alkaline province in Greenland and are able to reconstruct a recycled mantle source, thus alkaline rocks can be used to reveal crustal recycling through geological time.

Ultrack leverages candidate segmentations from multiple algorithms and temporal consistency across time points for robust, long-term 3D segmentation in challenging samples such as densely packed zebrafish, fruit fly and nematode embryos.

Factors limiting CNS remyelination with age are poorly understood. Here the authors show that aged Treg lose capacity to support CNS remyelination in mice, which can be restored in a young environment.

The circadian rhythm has been linked to cancer cell sensitivity to therapy but tools to understand this further are limited. Here, by combining live-cell imaging and computational tools, the authors develop a high-throughput deep-phenotyping approach to evaluate circadian rhythms and use it to determine time-of-day drug sensitivity in cancer cell lines.

In this study Fossati et al. demonstrate how co-fractionation mass spectrometry can be applied to systematically investigate pathogen proteome organization and host interactome plasticity upon Jumbophage infection of Pseudomonas aeruginosa.

Horses have lived in Iberia since the Ice Age. Using ancient genomes to study their history, Lira Garrido et al. reveal a local wild lineage lasting until Late Iron Age, and highlight the far-reaching influence of Iberian bloodlines across Europe and north Africa during the Iron Age and beyond.

Gold-standard evidence for correlates of protection is provided by analysis of a randomized phase 3 trial of Ad26.COV2.S for protection against moderate to severe-critical COVID-19 disease.

The expression of specific genes can be controlled by the combination of DNA-binding proteins, which determines their binding site selectivity. Here, simplified synthetic basic region leucine zipper-based peptides are induced to dimerize either through their C- or N-terminus, and thus are targeted to different DNA sequences.

Enabling concurrent, high throughput analysis of single nano particles would greatly increase the capacity to study size, composition and inter and intra particle population variance. Here, the authors present a comprehensive platform for single particle automated Raman trapping analysis without any target modification.

Inborn errors of the alternative NF-κB pathway in humans impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases

Fuchs and colleagues delineate a mechanism by which PARP11-mediated IFNAR1 loss sustains an immunosuppressive tumor microenvironment and show that PARP11 inactivation can enhance chimeric antigen receptor T efficacy in preclinical solid tumor models.

Tumour endothelial cell macropinocytosis is the dominant mechanism for nanoparticle entry into the tumour. Enhanced nanoparticle tumour accumulation may be due to upregulated macropinocytosis membrane ruffling compared with most healthy tissues.

Analysis of the pivotal phase 3 ZUMA-7 trial identifies tumor gene expression signatures that are uniquely predictive of anti-CD19 CAR T cell response and event-free survival in second-line treatment for patients with relapsed or refractory large B cell lymphoma.

The most common protein modification in eukaryotes is N-terminal acetylation, but its functional impact has remained enigmatic. Here, the authors find that a key role for N-terminal acetylation is shielding proteins from ubiquitin ligase-mediated degradation, mediating motility and longevity.

The vasculature produces strong endogenous contrast in magnetic resonance imaging (MRI). Here Desai et al. report genetically encoded imaging probes derived from the vasodilator, calcitonin gene-related peptide, which allows visualization of molecular events via haemodynamic changes in optical imaging or MRI.

BriSΔ, a SARS-CoV-2 variant from clinical isolate hCoV/England/02/2020, comprises a deletion in a spike cleavage site. The structure and molecular dynamics of this spike provides mechanistic insights into how the deletion modulates virus infectivity.

Staphylococcus CdnE03 cyclase recognizes structured RNA molecules produced by staphylococcal phages, triggering cyclic oligonucleotide production and, thereby, bacterial cell death—a mechanism of antiviral defence conserved across domains of life.

A study using a mouse solid tumour model suggests that adjusting the dosing frequency of the PI3Kδ inhibitor AMG319 in the treatment of human cancers could decrease tumour growth with fewer adverse effects.

Speleothem records from caves in Arctic Siberia allow for the reconstruction of multiannual air temperatures during the late Miocene (8.68±0.09 million years ago). These temperatures suggest that Eurasia was mostly permafrost-free during that time.

This study identifies candidate safeguard repressor transcription factors that repress alternate lineages in mature cell types and provides functional evidence that Prox1 performs such a function in hepatocytes during reprogramming, regeneration and in cancer.

Studies using viral coat glycoproteins show that alphaviruses can enter cells via the very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2), members of an evolutionarily conserved family of lipoprotein receptors.

Livestock greenhouse gas emissions are key to the sustainability of food systems. A spatially explicit analysis of global livestock supply chains shows large variability of nitrogen use efficiency across species, systems, production intensities and the origin and management of animal feed.

Semi-artificial photosynthetic systems combine natural and synthetic features to overcome limitations of each approach to produce solar fuels. Sokol et al. integrate a dye-sensitized TiO₂ photoanode with the natural machineries, photosystem II and hydrogenase, to split water without additional applied bias.

Recurrent metastatic rhabdomyosarcoma remains largely incurable. Here, the authors describe a child with metastatic rhabdomyosarcoma who has durable response to HER2-specific CAR T cells and shows endogenous immune reactivity.

Mechanical forces, along with gene regulatory networks and cell-cell signalling, play an important role in the complex organization of tissues. Here the authors describe devices that actively apply mechanical force to developing neural tube, demonstrating that mechanical forces increase growth and enhance patterning.

The main protease, a key enzyme of SARS-CoV-2, can protect itself from oxidative damage. Here, Reinke, Schubert, and colleagues used XFEL radiation to image the enzyme, revealing the disulfide and NOS/SONOS bonds that form in response to oxygen.

Restoring degraded food webs is a major conservation challenge and different approaches have been used. Here, modelling is used to show that restoring species together rather than sequentially leads to faster and less variable ecosystem recovery.

Antibiotic resistance can evolve through the stepwise accumulation of mutations. Here, the authors reconstruct the multistep evolutionary pathway for trimethoprim resistance and show that epistatic interactions increase rather than decrease the accessibility of each adaptive peak.

Fatty liver disease exacerbates atherosclerosis, but the underlying mechanisms remain unclear. Here, the authors show that D-dopachrome tautomerase (D-DT/MIF-2) acts as an atypical chemokine, promoting both atherosclerosis and hepatic lipid accumulation.

The W1282X nonsense mutation in the CFTR gene causes cystic fibrosis by reducing its mRNA and functional protein levels. Here the authors developed antisense-oligonucleotide cocktails that restore CFTR protein function by gene-specific stabilization of CFTR mRNA.

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.

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.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Disentangling causal interactions among biodiversity, ecosystem functioning and environmental factors is key to understanding how ecosystems respond to changing environment. This study presents a global scale analysis quantifying causal interactions and feedbacks among phytoplankton diversity, biomass and nutrients along environmental gradients of aquatic ecosystems.

Two-photon excitation is attractive for photodynamic therapy as it potentially allows deeper penetration within biological tissue and targeting with better precision. However, two-photon cross-sections of light-sensitive drugs are typically small, which has until now limited their practical utility. Now Anderson and colleagues have come up with a new family of light-sensitive drugs that are designed for efficient two-photon excitation. They demonstrate selective closure of blood vessels in mice using one of their new drugs.

A donor–acceptor molecule assembles with different molecular packing to form photocatalysts which selectively produce either H₂ or H₂O₂, depending on the aggregate structure, a proof-of-concept of photoactivity polymorphism.

The neuroimmune interactions driving secondary degeneration in the injured spinal cord remain elusive. Here, the authors reveal that damaged microglia release IL-1α, resulting in neutrophil infiltration and the loss of mature oligodendrocytes through astrocytic and endothelial IL-1R1 in mice.