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Flores et al. show that brain-penetrant eIF2B agonists suppress ISR activation in cellular and mouse models of ALS and reduce ISR biomarkers in humans, enabling further clinical studies of ISR inhibition in individuals with neurological diseases

Affinity chromatography allows for the separation of biomolecules such as proteins, based on a change in the chemical solvent composition and the resulting impacts on ligand binding. Here, authors introduce a physical principle by exploiting the light-dependent interaction between the Azo-tag and an α- CD chromatography matrix.

This study reports adhibin, a synthetic carbazole that suppresses the migratory and adhesive properties of cancer cells by a mechanism of targeted RhoGAP class-IX myosin inhibition and selective RhoGTPase interference, both translating into migrastatic activity, opening other perspectives in cancer therapy and basic research.

Using a new method to generate site-specific monoubiquitinated proteins, the authors find monoubiquitination has a site-specific effect on protein stability and proteasomal processing.

Mitochondria play a key role in cellular metabolism. Here, authors develop a Variational Autoencoder to design novel mitochondrial targeting sequences, validating them across several eukaryotic organisms and demonstrating their utility in metabolic engineering and protein delivery.

Directed evolution commonly relies on point mutations but InDels frequently occur in evolution. Here the authors report a protein-engineering framework based on InDel mutagenesis and fragment transplantation resulting in greater catalysis and longer glow-type bioluminescence of the ancestral luciferase.

Nitrous oxide is one of the main greenhouse gases emitted during biological wastewater treatment. This long-term multi-meta-omics analysis of a wastewater treatment plant identifies the main causes of nitrous oxide emissions and actionable mitigation strategies.

NanoLuc luciferase is a popular bioluminescent enzyme, but the molecular details of its mechanism of action on luciferins such as coelenterazine remained elusive. Here the authors use, protein crystal structures and biochemical analyses to provide an atomistic description of its catalytic mechanism and allosteric behaviour.

A combination of mouse model data and data from a randomized phase 2 trial in patients with breast cancer in remission demonstrates feasibility, safety and a reduction in residual tumor cells following treatment with hydroxychloroquine and/or everolimus.

BindCraft, an open-source, automated pipeline for de novo protein binder design with experimental success rates of 10–100%, leverages AlphaFold2 weights to generate binders with nanomolar affinity without the need for high-throughput screening.

Here the authors show that a Gamma-based subunit vaccine induces broadly neutralizing antibodies against SARS-CoV-2 variants including Omicron, induces cellular immune responses, and protects mice from infection with Omicron BA.5 SARS-CoV-2.

Many protein–protein interactions depend on Short Linear Motifs (SLiMs). In this study, the authors use large-scale binding assays, deep mutational scanning, and structural analysis to map SLiMs recognised by human cyclins and uncover the rules that determine their specificity and affinity.

Oncolytic virus holds potential as a cancer therapy, but further optimization is desirable. Here the authors screen existing drug to find talazoparib, a PARP inhibitor, synergizing with reovirus type 3 Dearing (RT3D) to induce cancer cell apoptosis, anti-tumor immunity, as well as control of primary and rechallenge tumor in mouse models.

Baker’s yeast is a workhorse of industrial biotechnology, but it is not suited to overproduce many bulk bioproducts, especially organic acids. Here, the authors identify Pichia occidentalis as an acid tolerant yeast and engineer it for the production of muconic acid using a newly developed genome editing toolkit.

A theoretical framework for quantum neural network (QNN) overparametrization, a phase transition in loss landscape complexity, is established. The precise characterization of the critical number of parameters offered is expected to impact QNN design.

Excess macrophage elastase MMP-12 is a major driver of chronic obstructive pulmonary disease. Here the authors show that the endolysosomal ion channel TRPML3 is a regulator of the cellular reuptake of MMP-12, thus neutralizing harmful MMP-12 in the lung.

Processes that occur after death have not received the same level of attention as the mechanisms of life. In this study, the authors show that bacteria have potentially evolved an altruistic trait to auto-degrade after death, thus permitting population nutrient recycling.

Sepsis induces a period of immunosuppression which can be problematic in the face of subsequent infectious challenge. Here the authors show the presence of PD-L1 expressing regulatory plasma cells that can inhibit T cells in a murine model and in patients with sepsis.

A combination of JWST/NIRCam observations and magnetohydrodynamic simulations indicates that frequent mergers with close companions give rise to bursty star formation and hence the unexpectedly high Lyman-α emission detected from early galaxies.

Mutations of the histone H3K36-specific methyltransferase ASH1L have been linked to several human diseases. Here, the authors report the mechanism by which three C-terminal domains in ASH1L regulate its enzymatic activity and interact with chromatin.

Cotranslational N-terminal methionine excision and acetylation of eukaryotic proteins on ribosomes is coordinated by the nascent polypeptide-associated complex.

Data from a variety of sources—including satellite, climate and soil data, as well as field-collected information on plant traits—are pooled and analysed to map the functional diversity of tropical forest canopies globally.

A market-based nitrogen insurance lets maize farmers cut excess fertilizer use without profit risk, as shown in simulations across 4,270 Illinois fields over 30 years and 33 nitrogen rates.

“In subarachnoid hemorrhage (SAH), therapies are limited and clinical outcomes remain disappointing. The authors show a contribution of the urotensin II system in microvascular changes, vasospasm, neuroinflammation and cognitive deficits post-SAH, primarily through meningeal cells and border-associated macrophages

Autophagosome tethering compounds (ATTECs) are small molecule degraders hijacking the autophagy system. Here, the authors show that current ATTEC ligands did not bind to their designated targets but establish good ligandability of ATG8 isoforms through fragment screening and docking.

The barren plateau problem represents one of the major bottlenecks for parametrized quantum circuits algorithms. Here, the authors study the known sources of BP using the lens of Lie algebraic theory, finding an expression of the variance of the loss function depending on the dynamical Lie algebra of the circuit.

Allergic inflammation is linked to asthma immunopathology and disease onset. Here the authors explore the use of a mucosal vaccine and show reduced immunopathology and asthma prevention in a murine model of allergic airway disease.

The authors here present a high-resolution structure of riluzole bound to a voltage-gated sodium channel. This identifies an intramembranous drug-binding site allowing the potent riluzole-induced enhancement of channel inactivation, normalising the hyperexcitable cellular states found in ALS models. This supports riluzole repurposing and aids future drug design efforts.

Leishmania use large (5–10 kb) transcriptional start regions, where the chromatin is highly enriched for acetylated histones, to drive the expression of polycistronic gene arrays. Here the authors show bromodomain-containing protein BDF5 is enriched at transcriptional start sites and its depletion leads to cell death in vitro and in murine infections, and they identify its interactors.

The ability to physically partition the human brain at a spatial resolution comparable to neuroimaging methods enabled the development of a brain-wide atlas of mitochondrial content, specialization and enzymatic oxidation and phosphorylation activities.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

Meng et al. develop the adeno-associated virus 9-based therapy CM-YAP^on to transiently and inducibly express YAP in the heart. In mice, CM-YAP^on promoted cardiomyocyte cell cycle reentry and reprogrammed the cardiac microenvironment. The CM-YAP^on gene therapy improved cardiac function after myocardial infarction (MI) and conferred cardioprotection before MI.

Directed evolution has emerged as a powerful tool for the identification of improved enzyme catalysts. Now, gel-shell beads are introduced as compartments that cage an enzyme with its encoding DNA, constituting a new genotype–phenotype linkage. Screening of 10⁷ gel-shell beads by flow cytometry leads to an improved phosphotriesterase bioremediation catalyst.

Discovery, biochemical and structural characterization of exoglycosidases from Akkermansia muciniphila reveals combinations that efficiently target extended A and B blood group antigens to produce ABO-universal blood for transfusions.

A trans-ancestry genome-wide association study of serum urate levels identifies 183 loci influencing this trait. Enrichment analyses, fine-mapping and colocalization with gene expression in 47 tissues implicate the kidney and liver as key target organs and prioritize potential causal genes.

Castells-Nobau et al. provide insight into how bacteriophages in the gut microbiome contribute to regulating food addiction by modulating tryptophan and tyrosine metabolism in the host.

Different phosphorylation patterns created by GRK2 and GRK5 on the C-terminal tail of ACKR3 lead to distinct structural arrangements and dynamics of G-protein-coupled receptor–arrestin complexes, potentially explaining diverse cellular outcomes.

A survey of SARS-CoV-2 RBD antibodies identifies those with activity against diverse SARS-CoV-2 variants and SARS-related coronaviruses, highlighting epitopes and features to prioritize in antibody and vaccine development.

A bacteriogenic strategy for constructing membrane-bounded, molecularly crowded, and compositionally, structurally and morphologically complex synthetic cells provides opportunities for the fabrication of new synthetic cell modules and augmented living/synthetic cell constructs.

The authors introduce a new spectroscopic technique for studying Higgs modes in superconductors and apply it to a cuprate superconductor. The method involves a soft quench of the Mexican-Hat potential, populating Higgs modes of different symmetries, which are then probed by non equilibrium anti-Stokes Raman scattering.

In this study, Green, Marttila, Kiweler et al. characterize one-carbon metabolism rewiring in response to a dual MTHFD1 and MTHFD2 inhibitor. This work provides insight into one-carbon fluxes, and reveals a previously uncharacterized vulnerability in cancer cells created by folate trapping.

Intermediate-coverage long-read sequencing in 1,019 diverse humans from the 1000 Genomes Project, representing 26 populations, enables the generation of comprehensive population-scale structural variant catalogues comprising common and rare alleles.

Cancer cells often acquire molecular patterns of fast-growing embryonic tissues to enable propagation and invasion, which distinguish tumour tissues from their healthy adult counterpart. Here authors develop antibody fragments which specifically target oncofetal chondroitin sulphate on the cancer cell surface and in the tumour stroma, with the antibodies achieving therapeutic effect in multiple mouse models in antibody drug conjugate and bispecific immune cell engager formats.

Continuous-flow biocatalysis with immobilized enzymes is a sustainable route for chemical synthesis, but inadequate biocatalytic efficiency caused by non-productive enzyme immobilization or enzyme-carrier mismatches presents a challenge for its application. Here, the authors report an approach for the fabrication of a high-performance enzymatic continuous-flow reactor via integrating scalable isoporous block copolymer membranes as carriers with an oriented one-step enzyme immobilization via a genetically fused material binding peptide.

Glycolytic enzymes are challenging drug targets due to their highly conserved active sites and phosphorylated substrates. Here, the authors identify fast acting allosteric inhibitors of Trypanosoma brucei phosphofructokinase that block trypanosome glycolysis and provide cure evidence in murine model.

A computational deep learning approach is used to design synthetic proteins that target the neosurfaces formed by protein–ligand interactions, with applications in the development of new therapeutic modalities such as molecular glues or cell-based therapies.

Macrophage-augmented organoids integrate macrophages into organoids that are cultured from human liver tissue for analysis of immune responses during three different viral infections.