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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.

Currently many of the time resolved serial femtosecond (SFX) crystallography experiments are done with light driven protein systems, whereas the reaction initiation for non-light triggered enzymes remains a major bottle neck. Here, the authors present an expanded Drop-on-Tape system, where picoliter-sized droplets of a substrate or inhibitor are turbulently mixed with nanoliter sized droplets of microcrystal slurries, and they use it for time-resolved SFX measurements of inhibitor binding to lysozyme and secondly, binding of a β-lactam antibiotic to a bacterial serine β-lactamase.

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.

Crossing the blood–brain barrier in primates is a major obstacle to gene delivery in the brain. Here an adeno-associated virus variant (AAV.CAP-Mac) is identified and demonstrated for crossing the blood–brain barrier and delivering gene sequences to the brain of different non-human primates species.

Miniaturization of devices and machines requires advanced lithographic techniques, whilst the high cost and complexity are the bottlenecks. Li et al.now show an approach for direct, arbitrary nano-patterning using self-propelled nanomotors acting as mobile nanomasks and near-field lenses.

The intercalated disc (ICD) is a membrane structure of the cardiac muscle involved in normal heart function. Here the authors report that knockdown of the ICD-bound transmembrane protein 65 results in impaired ICD structure, abnormal cardiac electrophysiology and cardiomyopathy in mice.

The performance of Li-ion batteries deteriorates at elevated temperatures due to increased activity of electrode materials and parasitic reactions. Here Yi Cui and colleagues report much-improved battery cyclability at 60 °C and use cryo-electron microscopy to shed light on the origin of the phenomenon.

Pycytominer is a user-friendly, open-source Python package that carries out key bioinformatics steps in image-based profiling.

Given its immunosuppressive effect in glioblastoma (GBM), targeting the TIGIT-CD155 axis presents an attractive therapeutic strategy. Here, the authors develop an adoptive natural killer (iNK) cells therapy with anti-CD155 synNotch-inducible CD73 antibody production to reverse the effect of TIGIT-CD155 signaling for the treatment of GBM.

Convolutional neural networks enable prediction of fluorescently labeled structures from three-dimensional time-lapse transmitted-light images. Applications include multiplexed long time-lapse imaging and prediction of fluorescence in electron micrographs.

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.

Dopamine receptor agonists are used for the treatment of various psychiatric diseases. Here, the authors screen approximately three million compounds and identify a novel class of D1R agonists that do not have a catechol scaffold and possess promising pharmacokinetic properties.

A study using a biochemical screen of 57 phages in two bacterial species identifies and characterizes proteins enabling phages to evade CBASS and Pycsar immune systems, and describes the mechanisms involved.

Federated ML (FL) provides an alternative to train accurate and generalizable ML models, by only sharing numerical model updates. Here, the authors present the largest FL study to-date to generate an automatic tumor boundary detector for glioblastoma.

This study reveals how Klotho and heparan sulfate glycosaminoglycan coreceptors enable FGF hormones to induce asymmetric 1:2 FGF–FGFR dimerization mandatory for FGFR kinase activation and hence signalling.

Enhancers for endodermal organs are primed at the chromatin level prior to lineage induction by FOXA pioneer transcription factors; how pervasive this is, is not well known. Here the authors show that only a small subset of organ-specific enhancers are bound and primed by FOXA prior to lineage induction, whereas the majority do not undergo chromatin priming and engage FOXA upon lineage induction.

Mutations in the gene HADHA result in mitochondrial tri-functional protein (MTP) deficiency and can result in sudden infant death syndrome for which there is no treatment. Here the authors show that the MTP deficient pathology in human cardiomyocytes leads to an abnormal cardiolipin pattern and suggests that cardiolipin affecting compounds may serve as a potential therapy.

How epigenetic regulation affects pancreatic development is unclear. Here, the authors show that the histone demethylase LSD1 regulates the epigenetic state of developmental enhancers during pancreatic specification and controls how these enhancers respond to extracellular signals, namely retinoic acid.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

A high-throughput screen of preclinical, investigational and FDA-approved drugs identifies compounds that possess antiviral and neuroprotective effects against Zika virus infection in human neural progenitor cells and astrocytes.

This Resource describes data, code and tools developed for the Human Reference Atlas and the Human BioMolecular Atlas Program for building and navigating a multiscale human atlas.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

An interim report from the GAIN/iCat2 study shows that molecular profiling of pediatric solid malignancies clarifies diagnostic classifications and provides opportunities for matched targeted therapy.

During acute HIV type 1 infection, a subset of γδ T cells that express Δ42PD1 are shown to home to the gut, where they activate innate immunity and inflammation through direct interaction of Δ42PD1 with Toll-like receptor 4. Blockade of this pathway reduces mucosal damage.

Traditional machine learning methods for drug development struggle with bioactivity prediction due to the limited number of compounds in each assay and assay incompatibilities. Feng et al. developed ActFound, a bioactivity foundation model trained by pairwise learning and meta-learning, that improves the accuracy and generalization of bioactivity prediction.

Heterogeneous water disinfection is a promising way to avoid secondary pollution, but it is not very efficient. The development of nanoflakes shows that a much higher efficiency than previously achieved can be achieved through solar-driven heterogeneous disinfection.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

Analysis of genomic and clinical features of acute erythroid leukemia in comparison to other myeloid disorders supports its distinct classification, defines subgroups and suggests therapeutic vulnerabilities.

Serine synthesis from glucose is required even when serine is available from the environment. Here, the authors explain this paradox by showing that the enzyme PHGDH enables nucleotide synthesis by coordinating anabolic fluxes related to central carbon metabolism, independent of its role in serine production.

A large-scale genomics study shows that the cell of origin and founding mutations determine disease subtype and lead to the expression of multiple haematopoietic lineage-defining antigens in mixed phenotype acute leukaemia.

The authors here report an ultrathin ionomer membrane as an artificial solid-electrolyte interphase filter that minimizes parasitic reactions and enables stable dendrite-free lithium plating-stripping cycles in a carbonate-based electrolyte. The protected anodes exhibit outstanding coulombic efficiencies at room and elevated (50 °C) temperatures.

Cryo-electron microscopy is widely employed in structural biology and uses phase contrast imaging. Here, the authors employ electron ptychography, a quantitative phase retrieval method for high-contrast, low-dose phase imaging of cryo-state rotavirus and immature HIV-1 virus-like particles, and show that electron ptychography is more efficient for phase recovery than conventional phase contrast imaging.

The authors report that calcium channels with a mutation associated with Timothy syndrome cause activity-dependent dendrite retraction in rodent neurons and in induced pluripotent stem cell–derived neurons from individuals with Timothy syndrome. This retraction was independent of Ca permeation but was associated with activation of RhoA signaling.

SynapShot combines ddFPs with engineered synaptic adhesion molecules for real-time observation of the structural plasticity of synapses in cultured cells and animals.

The ability to target and manipulate specific neuronal populations is crucial for understanding brain function. In this report, the authors describe a novel virus that restricts gene expression to telencephalic GABAergic interneurons, allowing for morphological visualization, activity monitoring and functional manipulation of interneurons in mice and in non-genetically tractable species.

A nanoporous polyimide film filled with a solid polymer electrolyte has high ionic conductivity and high mechanical strength. An all-solid-state battery made with an approximately 10-μm-thick film shows good cyclability at 60 °C and no dendrite formation.

Manipulating liquids with tunable shape and optical functionalities in real time remains a great challenge. Here, the authors demonstrate electrotunable liquid sulfur microdroplets in an electrochemical cell and tune its characteristics in a fast, repeatable, and controlled manner.

Developing a stable metallic lithium anode is necessary for next-generation batteries; however, lithium is prone to corrosion, a process that must be better understood if practical devices are to be created. A Kirkendall-type mechanism of lithium corrosion has now been observed. The corrosion is fast and is governed by a galvanic process.

The solid-electrolyte interphase (SEI) is one of the governing factors for the reversibility of Li metal anode. Here, the authors reveal the impact of nitrate additive on the SEI in carbonate electrolytes, and demonstrate a method to overcome the solubility limitation of nitrate.

There is an intensive effort to develop stationary energy storage technologies. Now, Yi Cui and colleagues develop a Mn–H battery that functions with redox couples of Mn²⁺/MnO₂ and H₂/H₂O, and demonstrate its potential for grid-scale storage.

The efficient design of electrochemical CO₂ reduction catalysts requires high CO₂ concentrations on the catalyst surface. Here, Cui and co-workers make use of flexible, hydrophobic, nanoporous polyethylene membranes with good gas permeability to design a catalytic set-up that mimics the alveolus structure in mammalian lungs, achieving high activity and selectivity to CO.

A supercooled liquid phase of elemental sulfur can be grown electrochemically on two-dimensional materials. This phase has a markedly higher areal capacity than solid sulfur, with possible implications for future lithium–sulfur batteries.