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The precise mechanisms that cause human obesity remain unknown. Here the authors illustrate how increased expression of Cadm1, a mediator of synapse assembly, is relevant to weight gain. Reduction of Cadm1 in multiple brain regions promoted weight loss, and these observations provide insight into the neuronal pathways contributing to obesity.

Genomic analysis of 491 medulloblastoma samples, including methylation profiling of 1,256 cases, effectively assigns candidate drivers to most tumours across all molecular subgroups.

Researchers developed an open-hardware structured illumination microscopy add-on. This affordable upgrade provides super-resolution capabilities for normal optical microscopes. Detailed instructions enable easy reproduction to help democratize advanced microscopy.

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.

DNA-carrying nanoparticles can efficiently introduce leukaemia-targeting CAR genes into T cell nuclei, thereby inducing long-term disease remission.

Replication stress has been associated with transient remodelling of replication intermediates into reversed forks, followed by efficient fork restart. Here the authors systematically analyse the role of RAD51 paralogs in these transactions, providing insights on the mechanistic role of different complexes of these proteins.

Chordomas are rare bone tumors with limited therapeutic options. Here, the authors identify molecular alterations associated with defective homologous recombination DNA repair in advanced chordomas and report prolonged response in a patient treated with a PARP inhibitor, which later acquired resistance due to a newly gained PARP1 mutation.

Analysis of mitochondrial genomes (mtDNA) by using whole-genome sequencing data from 2,658 cancer samples across 38 cancer types identifies hypermutated mtDNA cases, frequent somatic nuclear transfer of mtDNA and high variability of mtDNA copy number in many cancers.

Selenium and copper are two essential trace elements whose homeostasis and distribution is regulated by hepatic release of selenoprotein P (SELENOP) and ceruloplasmin, respectively. Here, the authors show that excessive copper results in hepatic SELENOP accumulation in the trans Golgi which might limit the selenium transport to peripheral organs.

RNA variants derived from cancer-associated RNA editing events can be a source of neoantigens. Here, based on a proteogenomic pipeline combining DNA and RNA sequencing with MS-based immunopeptidomics, the authors identity and validate potential neoantigen candidates in patients with different tumor entities, highlighting RNA as important neoantigen source.

Uptake of vitamin B₁₂ is important for colonisation of the gut by Bacteroides species. Here the authors characterise B₁₂ uptake in Bacteroides thetaiotaomicron, mediated by outer membrane protein complexes consisting of surface-exposed BtuG lipoproteins and BtuB TonB-dependent transporters.

Baarlink et al. identify a transient pool of nuclear F-actin, the dynamics of which are controlled by cofilin-1 that accumulates after mitosis and is important for chromatin reorganization in G1.

Rapid developmental changes in the response properties of neurons in visual cortex enhance motion discriminability following eye opening. Here the authors show that increases in direction selectivity are accompanied by reductions in the density of active neurons and variability in their responses and levels of noise correlation, changes that depend on the nature of visual experience.

A computational approach to generate reference-free protein families from the sequence space in metagenomes reveals an enormously diverse functional space.

Droplet GaAs quantum dots are interconnectable sources of single photons. Near-identical photons from remote GaAs quantum dots now show an interference visibility of 93% with quantum entanglement between the separate photon streams from the two sources.

Characterisation of optical frequency electric fields and its integration within ultrafast currents in nanostructures is a crucial step for the development of petahertz electronics devices. Here the authors demonstrate singleshot measurement of the phase of a laser pulse with on-chip arrays of hundreds of metallic nanoantennas.

Stable epigenetic changes indicate the existence of an obesogenic memory in mouse adipocytes that primes cells for pathological responses in an obesogenic environment and potentially contributes to the problematic ‘yo-yo’ effect often seen with dieting.

TROVE2, a gene implicated in inflammatory response and autoimmunity, is also associated with enhanced memory for emotionally charged events in post-traumatic stress disorder.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with poor prognosis. Here, the authors show that deficiency of the E3 ubiqutin-protein ligase Nedd4-2 in airway epithelial cells causes IPF-like disease in adult mice. This model may aid studies of the pathogenesis and therapy of IPF.

Analyses of primary and relapse samples of embryonal tumours with multilayered rosettes provide insights into the molecular mechanisms that underlie the development and opportunities for the treatment of this deadly disease.

Transcranial brain stimulation is used to treat neurological and psychiatric disorders. Soekadar et al.describe a novel method that allows simultaneous measurements and transcranial brain stimulation of human oscillatory brain activity associated with motor actions in primary cortical brain regions.

Here, the authors show that replication protein A (RPA) tends to self-assemble into dynamic condensates, in a manner that is stimulated by ssDNA and regulated by RPA2 phosphorylation. RPA condensates are functionally important for telomere clustering and RAD52-dependent telomere maintenance.

By measuring metabolic and biosynthetic activity with cell cycle progression, Litsios et el. uncover pulses in protein production rate that do not scale with cell size but drive cell cycle entry in budding yeast.

Exosomes mediate cell-to-cell communication by transporting proteins, mRNAs, and miRNAs but the mechanisms of protein sorting to exosomes are poorly understood. Here, the authors uncover that ubiquitin-like 3 (UBL3) regulates protein sorting to exosomes by acting as a posttranslational modification.

Microscopic imaging techniques have a high spatio-temporal resolution but, in living animals, are hampered by cardiac and respiratory motion. This paper describes a microscopic setup that allows fluorescent confocal imaging of the beating mouse heart over a period of several hours.

The nuclear factor kappa B subunit c-Rel acts as a master regulator of metabolism and signalling in epithelial cells and macrophages that drives inflammation and fibrogenesis in various models of fibrosis.

Characterization of RNA-binding proteins (RBPs) in tissues has been hampered by technical constraints. Here, the authors describe ex vivo eRIC, a method for global profiling of RBPs active in mammalian organs, and report comprehensive RBP atlases from mouse brain, kidney and liver.

Many biological processes are oscillatory and their rhythms shift in response to external stimuli. Here Kralemann et al. present a method to describe the sensitivity of an oscillator to external influences based on non-invasive observation of the system, and use it to study cardiac–respiratory interactions in humans.

Chlamydiae are sensitive to beta-lactam antibiotics, which target cell-wall peptidoglycan (PG), but it is unclear whether these bacteria possess PG. Pilhofer et al. now demonstrate that cell walls of a chlamydial species, Protochlamydia amoebophila, contain a PG layer.

The synthesis of amides is a key technology for the preparation of fine and bulk chemicals in industry. Here, the authors present the reductive amidation of esters with nitro compounds under additivesfree conditions as a robust methodology for amide synthesis.

The adhesion receptor CD2 plays an important role in the full activation of T cells. Dustin and colleagues show that CD2 occupies a region in the periphery of the immunological synapse where it amplifies cognate antigen signals, whereas the presence of PD-1 disrupts this effect.

The bacterial flagellar hook is made up of many copies of the protein FlgE. Here, the authors report the full structure of the hook from Campylobacter jejuni and show that its overall structure is different from that of the previously published filament.

Single-cell profiling studies of the human gastrointestinal tract are increasing, offering an excellent opportunity to generate the first Human Gut Cell Atlas. This Roadmap presents a structured direction towards this goal and provides a detailed overview of the major challenges.

The surfactant-like protein Ki-67 mediates the clustering of chromosomes during mitotic exit, which displaces large cytoplasmic molecules from the future nuclear space and thus enables the separation of cytoplasmic and nuclear components before the nuclear envelope reforms.

A protein interaction network constructed with data from high-throughput affinity enrichment coupled to mass spectrometry provides a highly saturated yeast interactome with 31,004 interactions, including low-abundance complexes, membrane protein complexes and non-taggable protein complexes.

High-energy interlayer excitons in van der Waals semiconducting transition metal dichalcogenides lie far above the bandgap and emit in the ultraviolet range.

Through archaeological excavation, morphological and proteomic taxonomic identification, mitochondrial DNA analysis and direct radiocarbon dating of human remains, a study reports the presence of Homo sapiens in Germany north of the Alps more than 45,000 years ago.

How arable farming affects soil fungal biogeography is poorly understood. Here, the authors find that prevalent fungal groups become more abundant, whereas rare groups become fewer or absent in arable lands across Europe, suggesting a biotic homogenization due to arable farming.

Paediatric high-grade gliomas with MYCN amplification (HGG-MYCN) are rare and highly aggressive. Here, the authors generate a mouse model for HGG-MYCN that can recapitulate the histological and molecular profiles of the human tumours, and perform high-throughput drug screening to identify potential treatment options.

Ionization delays from ethyl iodide around a giant dipole resonance are measured by attosecond streaking spectroscopy. Using theoretical knowledge of the iodine atom as a reference, the contribution of the functional ethyl group can be obtained.

The maintenance of bacterial and fungal activity is essential for ecosystem functioning, particularly in dry soils where the two phyla co-exist. Here, Worrich and colleagues show experimentally that mycelia traffic water and nutrients and thereby stimulate bacterial activity in stressful conditions.

We can often ‘fill in’ missing or occluded sounds from a speech signal—an effect known as phoneme restoration. Leonard et al. found a real-time restoration of the missing sounds in the superior temporal auditory cortex in humans. Interestingly, neural activity in frontal regions prior to the stimulus can predict the word that the participant would later hear.

Programmed ribosomal frameshifting (PRF) occurs in many viruses including SARS-CoV-2 to allow the translation of multiple proteins from a single transcript. Here, the authors identify the human short isoform of the zinc-finger antiviral protein (ZAP-S) as a direct regulator of PRF in SARS-CoV-2 that severely impairs SARS-CoV-2 frameshifting in cells and directly interacts with the SARS-CoV-2 RNA; interfering with the folding of the frameshift RNA element.