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Defective neurotransmission is a hallmark of spinal muscular atrophy (SMA). Here, the authors show that local presynaptic Munc13-1synthesis is defective in SMA and that modification of the Munc13-1 mRNA rescues presynaptic architecture and excitability.

Methane emission occurs in natural wetlands on a large scale, but the corresponding trace element emissions have not been studied. Here, the authors study selenium and arsenic emission in a pristine peatland and show that this causes large amounts of those trace elements to enter the biogeochemical cycle.

Substrate-specific proteases have an enormous potential in the life sciences, but tailoring their specificity remains challenging. Here, the authors describe a data-driven approach combining DNA recording and epistasis-aware deep learning to augment protease specificity engineering at large scale.

The targeted development of proteome-wide selective covalent probes remains a challenge. Here, the authors show the exploration of the natural product Sulphostin as a starting point for dipeptidyl peptidase 8 and 9 inhibitor development.

HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation.

Digital quantum simulations of Kitaev’s honeycomb model are realized for two-dimensional fermionic systems using a reconfigurable atom-array processor and used to study the Fermi–Hubbard model on a square lattice.

As proof of principle, an analysis using a suite of human-aligned immunocompetent mouse models of hepatocellular carcinoma identifies a promising therapeutic candidate, cladribine, which acts in a highly effective subtype-specific manner in combination with standard-of-care therapy.

Gq proteins are one of four major classes of G proteins; optogenetic receptors for selective and repetitive activation of Gq proteins with fast kinetics are lacking. Here the authors report UV light-dependent Gq signalling using human Neuropsin (hOPN5) and demonstrate its potential as an optogenetic tool.

Vascular cells express various G-protein-coupled receptors (GPCRs) with yet unknown function, among them orphan receptor GPR153. GPR153 is upregulated in injured vessels, where it promotes smooth muscle proliferation and endothelial inflammation, and its inactivation protects mice in models of vascular diseases.

The evolutionary origin of the enzyme-catalysed Krebs cycle is unclear. Here, the authors identify non-enzymatic intermediates that replicate key elements of the cycle, suggesting that inorganic catalysts may have driven the origin of metabolic processes.

K⁺ plays an important role in physiology and disease, but the lack of high specificity K⁺ sensors limits our understanding of its spatiotemporal dynamics. Here the authors develop genetically-encoded FRET-based probes able to quantify K⁺ concentration in body fluids, cells and specific organelles.

MethyLYZR, an epigenetic classifier of brain tumors, provides clinically relevant cancer classification results within 15 min of sequencing, with potential applications for neurosurgical intraoperative use.

Hofer et al. show that fasting promotes the synthesis of spermidine, which stimulates eIF5A hypusination to induce autophagy and increase lifespan in various species in a conserved manner.

A cell-based phenotypic screen led to the discovery of compounds called NVS-STGs, which bind to the N-terminal domain of STING and act as a molecular glue to induce higher-order oligomerization and activation.

In bacteria Zn2+-dependent deacylases are underexplored. Here, the authors identify bacterial deacylases, providing systemic structure-function analyses to reveal the basis of substrate specificity, acyl-chain preference and inhibition.

High-throughput screening identifies compounds that target insulin-degrading enzyme (IDE) and X-ray co-crystallography reveals how these compounds block insulin degradation by IDE but support its proteolysis of other substrates, including glucagon.

Despite advances in GPCR structures and peptide design, creating high-affinity ligands remains a challenge. Here the authors develop a computational method, successfully identifying peptide-based molecules for KOR: their platform shows promise for streamlined GPCR ligand discovery.

Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are characterized by the pathological accumulation of α-synuclein. Here the authors employ fluorescent probes, electron microscopy and NMR spectroscopy to study the properties of α-synuclein aggregates that were amplified from patient brain extracts and observe a greater structural diversity among PD patients compared to MSA patients.

Magic state distillation is achieved with logical qubits on a neutral-atom quantum computer using a dynamically reconfigurable architecture for parallel quantum operations.

The use of oncolytic viruses as a therapy for cancer is limited by mechanisms inhibiting viral replication in the tumor. Here, the authors show that a chemical derivative of itaconate, 4-octyl itaconate, increases oncolytic virus VSVΔ51 efficacy in various cancer models, through decreasing antiviral immunity.

Targeted protein degradation (TPD) is a key modality for drug discovery. Here the authors present the discovery and analysis of reversible DCAF1-PROTACs, which show efficacy in cellular environments resistant to VHL-PROTACs or with acquired resistance to CRBN-PROTACs.

Optical lattices have rapidly become a favoured tool of atomic and condensed-matter physicists. These crystals made of light can be used to trap atoms at very low temperatures, creating a workshop in which to pore over and tinker with fundamental properties of matter.

The authors present the results of a 24-month phase 2 study of AADvac1, a tau vaccine against Alzheimer’s disease. AADvac1 was safe and induced high levels of antibodies. In the whole study sample, there were no significant changes on clinical outcomes.

The gut commensal Akkermansia muciniphila regulates food allergy symptoms in a diet-dependent manner in mice.

CD19 CAR-T cells have achieved some success in treating myeloma patients despite the limited detection of the CD19 antigen. Here, the authors show using dSTORM that 10/14 myeloma samples studied express ultra-low levels of CD19, which are sufficient for engaging CAR-T cells in vitro.

α-Syn in CSF is a biomarker of neurodegenerative diseases; however, the detection of clinically relevant species is difficult. Here, the authors create a nanobody biosensor that reveals the presence of α-Syn in cells, which allow the detection of transmittable forms of α-Syn present in human CSF.

Obesity and a high-fat diet can lead to insulin resistance in a process involving macrophage-mediated inflammation of adipose tissue. Here the authors show that glucocorticoid receptor-deficient macrophages have an elevated inflammatory response which aggravates insulin resistance implicating that glucocorticoids promote insulin-sensitizing actions via adipose tissue macrophages during obesity.

The study describes the development and validation of Multi-Knock, a genome-scale clustered regularly interspaced short palindromic repeat toolbox that overcomes functional redundancy in plants by simultaneously targeting multiple gene-family members, thus identifying genetically hidden components.

Diphthamide is a post-translationally modified histidine residue present in animal and yeast TRANSLATION ELONGATION FACTOR2. Here the authors show that diphthamide modification of eEF2 is conserved in Arabidopsis thaliana and contributes to translational fidelity and growth via cell proliferation.

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.

Cognitive impairment in Alzheimer’s disease is associated with Tau at the postsynapse. We show that multivalent Tau interactions arrest in vitro condensates and clusters mimicking the postsynaptic density that may result in synaptic dysfunction.

Murphy and colleagues generate an inhibitor of the lipid kinase VPS34, which they use to uncover autophagy substrates. One of their targets, NCOA4, regulates iron homeostasis by binding ferritin heavy chain-1 and targeting ferritin to autolysosomes.

Established bacterial glycoengineering platforms limit access to protein and glycan substrates. Here the authors design a cytoplasmic protein glycosylation system, Glycoli, to generate a variety of multivalent glycostructures.

A chemical screen identified BET bromodomain inhibitors as promoters of keratinocyte regenerative function and skin wound healing. Specifically, low-dose transient treatment with BET inhibitors imposes an activated, migratory state in keratinocytes.

Jungnickel, Guelle et al. use metabolomics, electrophysiology and cryo-EM approaches to show that MFSD1 is a lysosomal dipeptide uniporter, which provides an additional route to recycle lysosomal proteolysis products to lysosomal amino acid exporters.

ASCC3 is a multi-functional helicase that contains two consecutive Ski2-like helicase units. Here, the authors show that ASCC3 can unwind DNA by threading one strand of a substrate duplex through both helicase units, supported by the TRIP4 protein.

Previous, a long-term evolution experiment in E.coli resulted in spontaneous emergence of ecotypes that coexisted for more than 14,000 generations. Here, the authors show that the emergence and persistence of this phenomenon results from two interacting trade-offs, rooted in biochemical constraints.

The RNA endonuclease CPSF3 was identified as the cellular efficacy target of the small molecule JTE-607, revealing pre-mRNA processing as a vulnerability in cancers such as Ewing’s sarcoma that are characterized by aberrant transcription.

A several-fold reduction in temperature is accomplished using a neutral-atom Hubbard quantum simulator by transforming a low-entropy product state into strongly correlated states of interest via dynamic control of the model parameters.

In 2002, an experiment with ultracold atoms emulated a textbook condensed-matter physics phenomenon: the phase transition from a superfluid to a Mott insulator. Two decades later, Immanuel Bloch and Markus Greiner ponder how far quantum simulation with ultracold atoms has come.

SARS-CoV-2 mutations associated with the escape from antibody-mediated neutralization have been widely reported. Here, in a patient with defective antibody responses, the authors find a potential association between SARS-CoV-2 mutations and CD8 T alterations to implicate possible contributions of CD8 T cells in evasion of SARS-CoV-2 from host immunity.

The identification of treatments that selectively co-inhibit cancerous cell populations remains a challenge. Here, a machine learning approach, scTherapy, leverages single-cell transcriptomic profiles to prioritize multi-targeting treatment options for individual patients with hematological cancers or solid tumors.

Unconventional protein secretion emerges as an important mechanism in aggregate-prone protein removal. Here, the authors demonstrate that Plekhg5 mediates the unconventional secretion of Sod1 by presynaptic secretory autophagy.

A study presents an approach to establish and track a new endosymbiotic partnership by implanting bacteria in a non-host fungus and shows that stable inheritance of the implanted bacteria is possible with positive selection.

Men are at a greater risk to develop Parkinson’s disease (PD). However, Hefeng and team revealed enhanced cytotoxicity and terminal differentiation in CD8 T cells of early-to-mid stage idiopathic PD, especially for females, using systems immunology.