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Chimeric antigen receptor (CAR) T cell anti-cancer therapies might result in toxic side effects. Here the authors present a strategy based on the modulation of CAR T cells via administration of a bispecific adapter that target them to cancer cells, resulting in diminished CAR-T cells toxicity and enhanced solid tumor eradication.

A whole-genome sequencing analysis of 100 pancreatic ductal adenocarcinomas has discovered known and newly identified genetic drivers of pancreatic cancer; these genetic alterations can be classified into four subtypes, which raises the possibility of improved targeting of clinical treatments.

Hematoxylin and eosin (H&E) staining is a widely used method in histopathology, but it cannot directly inform about specific molecular markers. Here, the authors present ROSIE, a deep-learning framework that computationally imputes the expression and localisation of dozens of proteins from H&E images.

Palmitoylation at C64 in stimulator of interferon genes (STING) is reported and, along with engagement of C91, is involved in dynamic cross talk with C148 to alter STING oligomer states and ultimately control STING activation.

Here, Isaacs, Nieto and Zhang et al. discover a potent nanobody and engineer a dual-action antibody that targets two viral proteins, offering strong protection against Nipah and Hendra viruses while preventing viral escape, potentially contributing to future treatments.

Resilience planning and action is limited to communities with significant technical and administrative capabilities. Engaging communities to co-produce research enables a more equitable distribution of needed tools. A national Community Resilience Extension Partnership linking scientists with place-based planners and emergency managers provides the research-to-practice infrastructure for equitable development of community resilience science and technology.

Cell state plasticity of neuroblastoma cells is linked to therapy resistance. Here, the authors develop a transcriptomic and epigenetic map of indisulam (RBM39 degrader) resistant neuroblastoma, demonstrating bidirectional cell state switching accompanied by increased NK cell activity, which they therapeutically enhance by the addition of an anti-GD2 antibody.

Quantitative multi-omics profiling of HDAC inhibitor responses in non-isogenic cancer cell lines reveals shared and divergent molecular remodeling. Responses highlight cell-type-dependent and -independent epigenetic drug mechanisms of action.

Sertraline (Zoloft) and fluoxetine (Prozac) are selective serotonin-reuptake inhibitors (SSRIs) that are widely prescribed to treat depression. They bind to the presynaptic plasma membrane serotonin transporter (SERT) and inhibit serotonin uptake. Both these drugs possess halogen atoms, but the structural basis for the specificity of SERT for these inhibitors was not known. Zhou et al. now report the crystal structure of LeuT, a bacterial SERT homolog in complex with three different SSRIs. The halogen atoms of all three bind within exactly the same pocket of LeuT, and mutations within this pocket in SERT markedly reduce the transporter's affinity for SSRIs but not for tricyclic antidepressants.

The X-ray crystal structure of a rat neurotensin receptor in complex with the C-terminal portion of neurotensin is presented; this is the first structure of a member of the β group of class A G-protein-coupled receptors.

By demonstrating a computational approach to restore the clinical efficacy of a COVID-19 antibody, the potential to rapidly update clinical antibodies is explored.

Anbazhakan et al. use whole-organ imaging and three-dimensional computational fluid dynamics modeling to define spatial architecture and predict blood flow through collaterals in neonate and adult mouse hearts after injury, and compare their findings to the functionality of collaterals in human adult and fetal hearts.

Understanding how copper nanoparticles evolve under electrochemical conditions is crucial for the development of selective CO₂ reduction electrocatalysts. Here the authors prepare well-defined nanocrystals and use advanced operando imaging and spectroscopic techniques to reveal the Cu–CO species-driven dynamic evolution of Cu electrodes.

A non-precious metal cobalt phosphide hydrogen evolution catalyst is found to be active and durable in a commercial-scale polymer electrolyte membrane electrolyser.

The antibiotic D-cycloserine (DCS) targets the peptidoglycan biosynthesis enzyme D-Ala-D-Ala ligase (Ddl). Here the authors reveal the DCS inhibitory mechanism by determining the structure of E. coli DdlB with a phosphorylated DCS molecule in the active site that formed in crystallo and mimics the D-alanyl phosphate intermediate.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

Importin α isoforms regulate the nuclear import of different cargo proteins but the mechanisms conferring isoform specificity are not fully understood. Here, the authors study the interactions of importin α1 and α3 with two viral cargos, elucidating the structural basis for isoform-specific cargo recognition.

The ability to assemble weakly-interacting subsystems is a prerequisite for implementing quantum-information processing. In recent years, molecular nanomagnets have been proposed as suitable candidates for qubit encoding and manipulation, with antiferromagnetic Cr₇Ni rings of particular interest. It has now been shown that such rings can be chemically linked to each other and the coupling between their spins tuned through the choice of chemical linker.

This Perspective reviews computational methods for cross-species knowledge transfer and introduces ‘agnology’, a data-driven concept of functional equivalence independent of evolutionary origin.

De novo designed interleukin-4 mimetics were engineered that induce biased signaling activation and exhibit high thermal stability. These mimetics offer insight into cytokine signaling and can be directly incorporated into 3D-printed biomaterials

Single-cell multimodal data has the potential to unveil noncoding disease mechanisms. Here, authors introduce GrID-Net, a graph-based Granger causal approach that links noncoding variants to genes by exploiting the time lag between epigenomic and transcriptional cell states.

Here the authors isolate monoclonal antibodies specific for Plasmodium vivax apical membrane antigen 1, and characterize the epitope of one antibody that inhibits invasion of reticulocytes and hepatocytes, and reduces liver infection in a mouse model.

Combining structural, biochemical, cellular and in vivo assays, the authors uncover the mechanism for capture and multisite phosphorylation of lethal (2) giant larvae by the atypical protein kinase C and partitioning-defective protein 6, revealing the basis for their mutual antagonism underpinning cell polarity.

This study introduces an indentation-based method to measure hardness across eleven decades of strain rate data, revealing a transition from thermally activated flow to phonon drag plasticity, using fully self-consistent data from a single material surface.

Structural and kinetic analyses of the transcriptional repressor SqrR in multiple states indicate that its persulfide selectivity is determined by structural frustration in the disulfide form, favoring formation of the tetrasulfide-bridged product.

One picosecond after photoactivation, isomerized retinal pulls away from half of its numerous interactions with its binding pocket, and the excess of the photon energy is released through an anisotropic protein breathing motion in the direction of the extracellular space.

Manju Kurian and colleagues report heterozygous variants in KMT2B in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance. Their findings highlight a clinically recognizable form of dystonia and demonstrate a crucial role for KMT2B in the physiological control of voluntary movement.

Paterson and Yu et al. demonstrate that loss of the RNA alternative splicing factor RBFOX2 in the liver during a lipogenic diet leads to dysregulation of liver lipid and cholesterol homeostasis through a specific alternative splicing programme, which includes a splice switch of the high-density lipoprotein receptor gene Scarb1.

A new method based on protein engineering to trap an intact complex between Siz1, SUMO-bound E2, and PCNA for structure determination.

Cancers often harbor mutations in genes encoding important regulatory proteins, but therapeutic targeting of these molecules proves difficult due to their high structural similarity to their non-mutated counterpart. Here authors show the engineering of T cell engaging bispecific protein able to selectively target cancer cells with a high-frequency mutation in the KRAS oncogene.

Here the authors use mRNA display to discover peptide inhibitors of BamA, an essential factor that catalyzes the membrane insertion of bacterial outer membrane proteins. They show that three peptides are antibacterial and inhibit BamA activity by a unique mechanism.

Structural characterization of the bifunctional enzyme linalool dehydratase isomerase and exploration of its substrate scope demonstrate its potential for catalyzing desirable transformations of various tertiary alcohols.

Microrchidia CW-type zinc finger protein 2 (MORC2) is an effector of epigenetic silencing by the human silencing hub (HUSH). Here the authors present the crystal structures of MORC2 and disease-causing MORC2 mutants and give mechanistic insights into how MORC2 mediates HUSH-dependent silencing.

Knowledge of the molecular mechanisms of activation of Clostridium difficile toxins will significantly enhance the ability to design specific anti-virulence therapies. Using activity-based chemical probes in combination with other techniques, this study reveals mechanistic insights into how inositol hexakisphosphate binding at the active site of the cysteine protease domain shifts the conformational equilibrium towards an active conformer.

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 two-bit magnetic memory is demonstrated, based on the magnetic states of individual holmium atoms, which are read and written in a scanning tunnelling microscope set-up and are stable over many hours.

Store-operated Ca²⁺channels (CRAC) are involved in several cellular functions. Here the authors identify a hydrophobic gate in the CRAC pore and show that CRAC activation by STIM1 involves rotation of the pore helix that hydrates this region to allow ion passage through the pore.

Phosphorene nanoribbons demonstrate extraordinary magnetic properties, ranging from large internal fields in films to macroscopic alignment in solution, which can be coupled to photoexcitations that localize to the magnetic edge of these ribbons.