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The authors identify defective viral particles, in people with non-suppressible HIV-1, that can replicate through superinfection and interfere with the wild-type virus. However, they show no evidence of these preventing disease progression in the individuals studied.

Immune receptors regulate immune responses and are key cancer immunotherapy targets. Here, the authors designed helical concave scaffolds to bind convex sites in immune receptors, creating high-affinity protein binders for TGFβRII, CTLA-4, and PD-L1. Co-crystal structures confirmed their therapeutic potential.

In this study, the authors develop a flavivirus vaccine strategy by introducing mutations into envelope glycoproteins resulting in structural changes that conceal the ADE-prone fusion loop epitope. They show that the Zika virus-specific construct protects mice against viral challenge and prevents ADE by Dengue virus.

A fresh approach to protein design that incorporates excited intermediate states enables precise control over the lifetime of protein interactions, with potential applications in cell-signalling modulation and in biosensors and synthetic circuits.

Understanding how oil supply-side policies affect extraction, emissions and communities is important for the design of decarbonization pathways. Here the authors take a modelling approach to characterizing 2020–2045 decarbonization scenarios from various policies applied to California’s oil extraction.

Intravesical bacillus Calmette–Guérin (BCG) is an established bacterial immunotherapy for bladder cancer. Here, the authors develop a personalized platform to identify microbial product cocktails that promote immune cell recruitment, infiltration, and activation for improving bladder cancer treatment.

The hippocampus can replay long spatial sequences without ripples. When present, ripples cluster in spatially restricted zones as a function of replayed location that remap with barrier changes, implying a tagging role in consolidation.

Polymerization-inducing chimeras are a novel bifunctional modality that uses protein symmetry to sequester targets by forming insoluble supramolecular assemblies. This approach overcomes reliance on accessory proteins and differs functionally from conventional inhibitors.

In this work, authors study a molecular signature in STING protein that is critical for distinguishing activation from inhibition and demonstrates therapeutic potential in correcting STING-related mutations in autoimmune conditions like STING-Associated Vasculopathy with onset in Infancy (SAVI).

Candida albicans must adapt to hypoxia. Here, the authors discover the sterol C4-methyl oxidase (SMO) Erg251 is essential for extreme hypoxic growth, as well as virulence and colonization, and that SMO inhibitors have therapeutic potential.

In the adrenal cortex, cholesterol used for steroid production is stored in lipid droplets. The authors demonstrate here the importance of the transcription factor HHEX in maintaining glucocorticoid levels and protecting lipid droplets from androgen-induced lipid depletion.

PU.1^low CD28-expressing microglia may act as suppressive cells in Alzheimer’s disease, mitigating its progression by reducing neuroinflammation and amyloid plaque load, indicating potential immunotherapeutic approaches for treatment.

The SLC45A4 gene encodes a neuronal polyamine transporter and is linked to pain response in humans and mice.

A protein biomarker, the NOTCH3 extracellular domain, identifies individuals with idiopathic pulmonary hypertension, correlates with disease progression, improves mortality risk prediction and provides a readily implementable, noninvasive blood test for this disease.

Muscularis macrophages, housekeepers of enteric nervous system integrity and intestinal homeostasis, modulate α-synuclein pathology and neurodegeneration in models of Parkinson’s disease, and understanding the accompanying mechanisms could pave the way for early-stage biomarkers.

Computational methods to analyse 3D organoids in high-throughput and with high cellular resolution remain scarce. Here, the authors propose Cellos, a high-throughput pipeline for 3D organoid segmentation using classical algorithms and a trained convolutional neural network.

There is still a need for effective HIV vaccines. In this phase I clinical trial, the authors show that an HIV-1 vaccine candidate, ConM SOSIP.v7, is well-tolerated in HIV-negative adults and that it elicits a strain-specific neutralising antibody response that differed between female and male participants.

Arrayed and pooled high-throughput screening is crucial for drug discovery and CRISPR functional genomics. Here, the authors present dFLASH; a dual FLuorescent transcription factor Activity Sensor for Histone-integrated live-cell reporting for high performance screening applications across numerous pathways and screening contexts.

A common mechanism by which cancer cells acquire resistance to chemotherapeutics is through the overexpression of efflux pumps, but platinum anticancer agents that crosslink DNA and interact with proteins are poor efflux pump substrates. Here, the authors design dual warhead drug conjugates by tethering a platinum pharmacophore to the doxorubicin backbone, which exhibit the activity of both parent anticancer compounds and can overcome drug efflux effectively due to covalent binding to intracellular biomolecules.

Candida auris is a fungal pathogen notorious for persistent skin colonization and transmission in healthcare settings. Here, Zhao et al. explore the mechanisms driving pathogen’s adherence to skin, involving a conserved adhesin, as well as the potential of collagen coatings as a strategy to reduce C. auris adherence to abiotic surfaces.

The placenta plays vital roles in supporting fetal development. Here, Richards et al. develop a high-throughput bioprinted trophoblast organoid model to recapitulate the microenvironment of the early placenta, enabling investigation of placenta development and evaluation of therapeutics for placenta dysfunction disorders.

Brown et al. show that mouse islet progenitors with different transcriptomes produce distinct β-cell subtypes and maternal diet alter the subtype proportions. Similar β-cell subsets exist in humans, with a subset enriched in genes related to β cell function reduced in diabetes.

Adjuvants are an important component of modern vaccines. Here, the authors employ a phenotypic screen of ~200k compounds and identify PVP-057, a TLR3 agonist with a simple scalable 3-step synthesis, as an adjuvant that induces durable humoral and cellular immunity to varicella-zoster virus (VZV) gE in mice.

In chemical-genetic and lipidomics analyses, the clinical candidate oncology drug tegavivint induced an unconventional form of nonapoptotic cell death that required the lipid metabolic enzyme trans-2,3-enoyl-CoA reductase.

Metagenomes from hydraulically fractured wells over time identified viral operational taxonomic units predicted to actively infect dominant bacteria, and in vitro experiments show that viral lysis of these hosts can release metabolites important for fermentation.

Here the authors show that persistent antigen stimulation drives the generation of CD8⁺ tissue-resident exhausted T cells with distinct developmental origins, function and therapeutic responsiveness when compared to CD8⁺ tissue-resident memory T cells.

A PICALM allele associated with increased risk of late-onset Alzheimer’s disease has a microglial-specific role in lipid droplet accumulation.

The reconstitution of complex biological processes in cell-free systems can support the detailed characterisation of biochemical mechanisms which are difficult to probe in vivo. Here authors present an all-cell-free T7 phage cycle, consisting of cell-sized liposomes encapsulating a cell-free gene expression reaction and a phage receptor at the membrane.

Serological detection of antibodies against SARS-CoV-2 can help establish rates of seroconversion. Here the authors develop a red cell agglutination test to detect antibodies against the receptor binding domain for distribution free of charge to qualified research groups.

This study reports coherent Aharonov–Bohm interference, including statistical phase contributions, in a Fabry–Pérot interferometer at two even-denominator fractional quantum Hall states in high-mobility bilayer-graphene van der Waals heterostructures is reported.

This study reveals that rising temperatures and decreased precipitation levels increase walking time for fetching drinking water in Sub-Saharan Africa. Rural areas are most affected, but community electricity access mitigates the walk time burden.

Methods for the systematic synthesis and evaluation of large numbers of transition metal complexes at a time are still limited. Here, the authors report a high-throughput method to create and test hundreds of metal complexes, revealing potent new metalloantibiotics and a highly active iridium catalyst.

Zuhra and Petrosino et al. report evidence that cyanide acts as a regulatory gasotransmitter in mammalian cells, where it is shown to affect cellular bioenergetics, most likely via protein S-cyanylation.

Intramyocardial injection of synthetic mRNA coding for the embryonic T-box transcription factor 18 gene generates rate-adaptive cardiac pacing and limits innate and inflammatory immune responses, as shown in rodents and pigs.

Schilperoort et al. explore the mechanisms underlying dynamic changes in macrophage metabolism that support efferocytosis. They show that transient glycolysis and subsequent lactate production are necessary to execute continual efferocytosis, as opposed to prolonged glycolysis observed in pro-inflammatory macrophages.

Molecular glues are monovalent compounds that can recruit a protein of interest to an E3 ligase so the protein of interest can be targeted for degradation. Here, Hughes et al. identify a molecule that selectively and potently degrades BRD9.

This study demonstrates the capability of deep learning protein design models in generating functionally validated β-strand pairing interfaces, expanding the structural diversity of de novo binding proteins and accessible target surfaces.

Paul and colleagues report the development and characterization of an antibody–drug conjugate targeting TRBC2 for the treatment of T cell malignancies.

Measuring the bulk power laws of Luttinger liquids in semiconductors remains challenging. Here, the authors demonstrate the dominance of the end-tunneling effect in two fairly distinct Luttinger liquids coexisting in a single quantum wire.

A rationally designed assay detects granzyme A activity by integrating peptide-based GzmA-targeted inhibitors and probes with chemiluminescent reporters to monitor inflammatory bowel disease.

Biomolecular condensates of Eps15 recruit and assemble clathrin. In turn, clathrin assembly restricts condensate growth while imposing the preferred curvature of the clathrin lattice.

Hormone-producing enteroendocrine cells (EEC) regulate of energy homeostasis and gastrointestinal function. Here the authors report protocols to induce human intestinal stem cells into EECs producing multiple gut hormones, including SST, 5-HT, CCK and GIP, using directed differentiation with small molecules targeting FOXO1, JNK and CB1 signalling.

Fluorescent protein reporters based on GFP exist, but have intrinsic disadvantages. Here the authors incorporate pH, Ca²⁺ and protein–protein interaction sensing modalities into de novo designed mini-fluorescence-activating proteins (mFAPs), with increased photostability and smaller size, which bind a range of DFHBI chromophore variants.

SIVmac239 infection of macaques is a favored model of human HIV infection, but antibody-mediated protection for SIVmac239 is insufficiently understood. Here, Zhao and Berndsen et al isolated nAbs and confirmed protection against SIVmac239 infection in passive transfer studies in macaques. The nAb was used to provide the first high-resolution structure of a rhesus SIV trimer by CryoEM. Analysis of the glycosylation pattern of this SIV trimer suggests a denser glycan shield on Env for rhesus SIV compared to chimpanzee SIV or HIV-1, which partially explains the poor nAb response of rhesus macaques to SIVmac239 infection.

Improved vaccines and antivirals are needed for many enveloped viruses. Here, the authors identify sulfur-based small molecules that disrupt viral membrane properties, inhibiting fusion and entry, and safely inactivate influenza virus. The resulting inactivated influenza vaccine is protective in mice.

The xylosyltransferase isoenzymes XT1 and XT2 catalyze the first glycosylation step in the biosynthesis of proteoglycans. Now, bump-and-hole engineering of XT1 and XT2 enables substrate profiling and modification of proteins as designer proteoglycans to modulate cellular behavior.