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Here the authors combine a deep generative model with structure-based drug design and prospectively validate functionally active, nanomolar, A_2A adenosine receptor ligands and solve their crystal structures to close the Artificial Intelligence Structure-Based Drug Design loop.

The identification of cellular targets for natural products that potently inhibit the growth of cancer cell lines implicates oxysterol-binding proteins in the growth of cancer cells. These natural products, termed ORPphilins, also affect sphingomyelin biosynthesis.

A layered hybrid lead halide intercalated with Ru(bpy)₃²⁺ is assembled through Pb²⁺-carboxylate coordination. The material has broad visible light absorption and drives photocatalytic CO₂ reduction to CO with a quantum yield of ~3.0% at 500 nm.

A knockout study of all human glycosyltransferases encoded in CHO cells provides a guide to producing proteins with desired glycosylation patterns.

Ewing sarcoma tumour cells frequently metastasize to the bone but the molecular mechanisms governing this process are not well understood. Here, the authors show that neuropeptide Y/Y5 receptor pathway is activated in the hypoxic tumour microenvironment, which results in cytokinesis defects and chromosomal instability, leading to bone invasion.

EGFR is a primary target molecule in drug exploration for cancer therapeutics. Here, the authors show a demonstration of single-molecule tracking-based drug screening for EGFR, proving the selectivity for tyrosine kinase inhibitors and potential to find drugs with previously untargeted mechanisms.

Instrumental to the migration of antigen-scavenging immune cells, the lymphatic vessel entry receptor LYVE-1 interacts with the hyaluronan glycocalyx, anchored by the leucocyte hyaluronan receptor CD44. Here, dynamic force spectroscopy, crystal structures and MD simulations provide mechanistic insights.

The secretory pathway is used in the production of most biopharmaceuticals, but the associated biosynthetic costs are little understood. Here, the authors integrate the core secretory pathway into genome-scale metabolic models of human, mouse, and CHO cells, enabling in silico analysis.

Analysis combining multiple global tree databases reveals that whether a ___location is invaded by non-native tree species depends on anthropogenic factors, but the severity of the invasion depends on the native species diversity.

Multiomics reveals that sexual differentiation in human malaria parasites, which is essential for transmission, is regulated by competition between phospholipid metabolism and histone methylation.

Electrolyte interactions critically govern battery performance yet lack precise design principles. The authors introduce interaction motif descriptors to design an electrolyte enabling 99.7% Li-metal Coulombic efficiency for 4.5 V batteries.

Precise and scalable regulation of gene expression in mammalian cells is challenging. Here, the authors created a highly tunable CRISPR-based synthetic transcription system for programmable control of mammalian gene expression and cellular activity.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

Yeast surface display technology enables real-time monitoring and effective screening of libraries of millions of disulfide-cyclised peptides against diverse protein targets. Selected ligands are characterised rapidly and quantitatively without the need for chemical synthesis and purification.

Two subclasses of ligand-gated ion channels (ASIC3 and P2X3) are both present at sensory neurons and might be therefore subject to receptor crosstalk. Here authors use electrophysiology, biochemistry and co-immunoprecipitation to show that the two ion channels interact and affect P2X3 currents.

Manipulating the carbon-carbon coupling pathway in CO₂ electroreduction is vital yet challenging. Here, by studying two model copper-based catalysts with distinct ethylene and ethanol selectivity, authors investigate the mechanistic origins for symmetric and asymmetric carbon-carbon coupling.

Prasad et al. assess four therapeutics in preventing lethal disease in an established nonhuman primate model of Ebola virus infection. They find that each therapy results in ~ 40% survival, suggesting the use of alternative strategies, such as combining therapeutics to combat Ebola.

Click-ExM uses click-chemistry-based labeling to increase the versatility of expansion microscopy. Click-ExM enables imaging of numerous classes of biomolecules including lipids, glycans, proteins, DNA, RNA and small molecules.

In this partially randomized clinical trial, the authors find that an orally inhaled Ad5-nCoV booster is associated with a lower incidence of symptomatic COVID-19 during the following 6 months compared with controls who haven’t received a booster. Intramuscular administered Ad5-CoV booster is associated with reduced COVID-19 incidence as well.

The mechanisms driving epithelial regeneration in the colon are not well understood. Here, the authors show that IFN-γ, produced by immune cells in response to chemically induced colitis, acts as a central driver of crypt reorganization by inducing apoptosis and extrusion of BMP2-expressing colonocytes.

The anti-tumour effect of immune checkpoint inhibitors is potentiated by CD137 agonists in preclinical models, but translation of these results to the clinical practice is hampered by toxicity. Authors describe here a human CD137xPD-L1 bispecific antibody with improved anti-cancer activity whilst maintaining low toxicity in non-human primates.

GABA_B receptors mediate the effects of the main inhibitory neurotransmitter in the brain. Here, authors identify the cytoskeletal protein filamin A as a key player that controls the exact ___location and function of GABA_B receptors at the cell surface.

Strong lasing effects similar to those in the optical regime can occur at 1.5–2.1 Å wavelengths during high-intensity XFEL-driven Kα₁ lasing of copper and manganese.

A genome-wide study by the Long COVID Host Genetics Initiative identifies an association between the FOXP4 locus and long COVID, implicating altered lung function in its pathophysiology.

Collagen can be a metabolic source to fuel cancer growth. Here the authors show that cell surface protein TEM8 mediates the binding and uptake of collagen in stromal cells and these cells processed the collagen to glutamine, providing an alternative energy source for tumour cells to grow.

The inhibitory receptor CTLA-4 recognizes two ligands on opposing antigen-presenting cells, CD80 and CD86. Sansom and colleagues show CTLA-4 captures ligands by transendocytosis, whereupon low-affinity CD86 releases CTLA-4 at low pH to promote CTLA-4 recycling; however, high-affinity CD80 remains bound and targets CTLA-4 for ubiquitination and destruction.

Species’ traits and environmental conditions determine the abundance of tree species across the globe. Here, the authors find that dominant tree species are taller and have softer wood compared to rare species and that these trait differences are more strongly associated with temperature than water availability.

The control of turbulent flows is crucial for improving efficiency in engineering systems. Here, authors show in a numerical simulation that using deep reinforcement learning to control surface actuators can successfully mitigate turbulent flow separation, paving the way for new advancements in turbulence control.

Mammalian orthoreovirus causes serotype-specific disease in the brain. Here, Shang et al. identify and characterise the role of paired immunoglobulin-like receptor B in reovirus attachment, entry and infectivity in the brain.

The combination of expansion microscopy with enhanced super-resolution radial fluctuations analysis enhances the image resolution of a conventional microscope to 25 nm in clinical and experimental samples.

A suite of generally applicable methods and tools, developed to enable single-molecule FRET-based studies of transmembrane proteins diffusing in the cell membrane of living cells, was used to study the oligomerization and dynamics of GPCRs.

TGFβ superfamily proteins can affect cellular differentiation, thermogenesis, and fibrosis in mammalian adipose tissue. Here the authors described a role for the TGFβ superfamily protein GDF3 in the regulation of lipolysis, glucose tolerance and glycemic variability in mice.

Programmed death-ligand 1 (PD-L1) is involved in the inhibition of antigen specific T cells via ligation of programmed death 1 (PD-1). Here, the authors show checkpoint inhibition by use of small molecule inhibition of PD-L1 which in a humanised mouse model was shown to restore T cell responses and reduced tumour burden.