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Increasing mitochondrial oxidative capacity and energy expenditure holds therapeutic potential for obesity and metabolic disorders. Here, the authors identify MTCH2 as a mitochondrial regulator of fatty acid oxidation via interaction with CPT1.

Comparative analysis of primary murine vascular cells sheds light on the roles of epidermal growth factor receptor, sex and the synergism of stressors for obesity-associated transcriptomic and phenotypic vascular alterations.

In this study, the authors assess the global response to the toxic aldehyde glyoxal (GO) in Pseudomonas aeruginosa, suggesting that GO controls quorum sensing during infection through a mechanism involving a novel protein, ArqI.

Injectable conductive hydrogels offer a promising alternative for tumor electrotherapy. Here, the authors develop highly conductive injectable bioresorbable soft electrode that enable minimally invasive glioblastoma electroimmunotherapy, achieving tumor ablation and robust immune activation.

Wireless magnetic control of gene expression in mammalian cells has been developed based on intracellular nanointerface and ROS-mediated signalling. The approach allows remotely tunable insulin release and regulates blood glucose in diabetic mice.

Circadian clocks integrate external environmental and internal physiological cues to generate oscillations of secreted endocrine signals. Here the authors build a melatonin-based circadian biomarker-driven gene switch in mammalian cells for type-2 diabetes treatment by oscillatory GLP-1 release.

Here, the authors develop hydrocarbon-stapled paxillin-mimetic peptides that act as selective and potent focal adhesion kinase (FAK) scaffold inhibitors to displace FAK from focal adhesions. Treatment shows reduced cancer cell survival in vitro and reduced tumor burden in vivo.

A population of TRAIL-positive astrocytes in glioblastoma contributes to an immunosuppressive tumour microenvironment and this mechanism can be targeted with an engineered oncolytic virus to improve outcomes.

Limited diagnostic capacity for asymptomatic individuals hinders malaria elimination efforts in Africa. Here, the authors present a near point-of-care method based on colorimetric LAMP detection that outperforms expert microscopy and commercial rapid diagnostic tests for Plasmodium detection in asymptomatic and submicroscopic individuals.

Development of a biosensor for GPCR trafficking to the lysosome combined with a genome-wide CRISPR screen identified DNAJC13 as a critical regulator of agonist-induced trafficking of the δ-opioid receptor to the lysosome.

The GAIN domain of adhesion G protein-coupled receptors, a class of biological mechanosensors, was thought to be sufficient for its self-cleavage. Here, the authors show that the event also depends on the seven-transmembrane region of the receptors.

The connection between classical neural networks and Gaussian processes is a fundamental result in machine learning. It has now been shown that many quantum neural networks converge to Gaussian processes, enabling their use for regression tasks.

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.

PARP enzymes play key roles in human biology, but their regulation remains poorly understood. This study shows that PARP15 is activated through dimerization of its catalytic domain and reveals how this event primes the domain for ADP-ribosyl transfer.

There has been growing evidence that strategies to circumvent the barren plateau problem in variational quantum computing might also kill potential quantum advantages. In this Perspective, the authors gather this evidence, discuss what is still missing to provide a definitive answer, and provide new research directions.

Silane, which is a precursor to the sandy surfaces of rocky planets and dusty clouds on gas giants, is seen directly in another world—a low-metallicity brown dwarf in which oxidation is slow and gas mixing is fast.

SCF–FBXO31 scans proteins for C-terminal amidation and marks them for subsequent proteasomal degradation.

Understanding the growth dynamics of GBMs can help expand therapeutic options. Here, authors use a cross-species computational approach to compare GBM cells to healthy neural stem cells, identifying predictors and modulators of tumour growth, including the Wnt antagonist, SFRP1, which stalls growth in preclinical xenograft models.

Post-translational modifications (PTMs) are important for the stability and function of many therapeutic proteins. Here, the authors develop a high-throughput workflow combining cell-free gene expression with AlphaLISA to rapidly characterize and engineer PTMs on both proteins and peptides.

Antisense oligonucleotide (ASO) cellular activity requires endosomal escape. Here, the authors show that disrupting Golgi-endosome protein AP1M1 enhances ASO activity by prolonging ASO endosomal residence and increasing the likelihood of endosomal escape.

The development of broadly neutralizing monoclonal antibodies is crucial in the fight against viral infections. Here, using combinatorial library technology, the authors identify 3D1, a monoclonal antibody with potential pan-inhibitory activity against a range of viral families, and provide structural analysis to reveal the basis of the broad cross-reactivity.

Here the authors show how the DNA-sensing cGAS–STING pathway activates NF-κB and inflammatory gene expression with delayed kinetics via post-Golgi endolysosomal signaling.

Endothermy facilitated mammalian species radiation, but the events leading to sustained thermogenesis are not clear. Here, the authors report functional brown adipose tissue in a protoendothermic mammal, linking nonshivering thermogenesis directly to the roots of eutherian endothermic evolution.

Current synthetic gene switches face limitations including cytotoxicity and long-term side-effects. Here, authors present an aspirin-activated system, demonstrating the regulation of insulin expression in diabetic mice, restoring glucose levels, alleviating pain, and reducing biomarkers of inflammation.

Zaman, Yang and Huang et al. demonstrate MDK’s suppressive effect on amyloid-β and its impact on amyloid burden and microglial activation in Alzheimer disease mice, highlighting its protective role in pathogenesis.

The authors develop and characterise a selective Greatwall inhibitor, C-604, and show that its cytotoxicity stems from PP2A-B55α hyperactivation. They identify B55α and Greatwall levels as biomarkers of responses to Greatwall-targeted therapy.

Human gut bacteria bioaccumulate per- and polyfluoroalkyl substances (PFAS), commonly known as forever chemicals, in intracellular aggregates. Colonization of gnotobiotic mice with bioaccumulating bacteria increases faecal PFAS excretion.

B cell maturation antigen (BCMA) has long been viewed as essential for plasma cell survival via APRIL-mediated signalling. Here, using two independent BCMA-deficient mouse models, the authors show that both the generation and long-term maintenance of plasma cells are unaffected by BCMA deficiency, and these plasma cells express normal levels of survival genes, thereby overturning the prevailing paradigm of the APRIL–BCMA axis as critical for plasma cell longevity.

A strategy for protecting redox-active ortho-quinones, which show promise as anticancer agents but suffer from redox-cycling behaviour and systemic toxicity, has been developed. The ortho-quinones are derivatized to redox-inactive para-aminobenzyl ketols. Upon amine deprotection, an acid-promoted, self-immolative C–C bond-cleaving 1,6-elimination releases the redox-active hydroquinone. The strategy also enables conjugation to a carrier for targeted delivery of ortho-quinone species.

ParABS systems partition chromosomal DNA and low-copy plasmids in bacteria. Here, the authors elucidate the mode of interaction between ParA and ParB and clarify how ParB stimulates the ATPase activity of ParA to drive the segregation process.

Ultrasensitive, real-time profiling of bio-analytes is a prerequisite for precision medicine. Here, the authors present a versatile bio-electronic interface (VIBE) to sense signaling cascade-guided receptor-ligand interactions and show that it can detect hormone levels in blood samples and differentiate individual metabolic conditions.

The RNA methyltransferase activity of SPOUT1/CENP-32 is crucial for accurate mitotic spindle organization. Here, the authors describe a neurodevelopmental disorder caused by bi-allelic pathogenic SPOUT1 variants with reduced activity and compromised function in spindle organization.

Lifetime-encoded materials are attractive as optical markers. Here, the authors report a design strategy for true orthogonality in encoding based on heterometallic rare-earth MOFs with independently variable lifetime and composition.

Cytoskeletal breakdown is a hallmark of synapse elimination. Here, the authors show that a post-translational modification on microtubules encodes activity-dependent signals instructing neuronal remodeling in the central and peripheral nervous system.

Amyloid self-assembly is linked to type 2 diabetes and Alzheimer’s disease. Here the authors designed constrained peptides which are nanomolar amyloid inhibitors of the key polypeptides IAPP and Aβ42 and act via supramolecular nanofiber co-assembly.

Targeted protein degradation (TPD) is a key modality for drug discovery. Here the authors present the discovery and analysis of reversible DCAF1-PROTACs, which show efficacy in cellular environments resistant to VHL-PROTACs or with acquired resistance to CRBN-PROTACs.

In this work, authors develop obex inhibitors that target a distinct binding pocket in the ATPase domain of Topoisomerase II. They demonstrate how Topobexin, a Topoisomerase IIβ - selective catalytic inhibitor, blocks conformational changes and protects against anthracycline cardiotoxicity.

Amyloid fibrils can adopt a range of distinct conformations, yet it is challenging to rapidly discriminate between these polymorphs. Now methods have been developed to screen large, diverse libraries of turn-on fluorescent dyes to rapidly identify probes that recognize fibril subsets.

By using cryo-EM and biochemical assays, Loeff et al. reveal the mechanistic basis for the protective function of the oxidoreductase PYROXD1 that maintains the activity of the tRNA ligase complex under aerobic conditions.

Pattern recognition receptors (PRR) critically modulate innate immunity. Here the authors show in cancer cells that interferon responses and anti-tumor immunity activated by dsRNA-induced PRR signaling is enhanced by palbociclib-induced ER stress, with epigenetic changes and altered antigen presentation potentially contributing to this effect.

Fragment-based drug design is an efficient yet challenging approach for developing therapeutics. Here, the authors employ structure-based docking screens of vast fragment libraries to identify inhibitors of 8-oxoguanine DNA glycosylase, a difficult drug target implicated in cancer and inflammation.

Lung and thymoma cancer patients often suffer from autoimmunity and related painful neuropathies. Here the authors show that patient-derived anti-CRMP5 autoantibody binds to rat dorsal root ganglia to cause pain, that immunizing rats with CRMP5 recapitulates these phenotypes, and that depleting rat B cells with anti-CD20 ameliorates related symptoms.

Maio et al. show that SARS-CoV-2 replication proteins contain iron-sulfur clusters that enhance RNA capping and are sensitive to redox changes, uncovering potential regulatory mechanisms and therapeutic targets in the viral life cycle.

Here the authors show that antibiotic resistance genes peak in the gut at the age of 6 months, and that beneficial bifidobacteria produce aromatic lactic acids that actively inhibit antimicrobial resistant bacteria, suggesting that boosting these microbes may help curb antimicrobial resistance.

The nuclear localization of metabolic enzymes is fascinating and in most cases remains a mystery. Here, Pardo Lorente and colleagues show that nuclear MTHFD2 is required for successful mitosis by controlling centromeric histone methylation.

Targeting cellular glucose metabolism is a therapeutic strategy in human diseases such as autoimmunity or cancer. Here, the authors demonstrate the druggability of phosphoglycolate phosphatase, and validate an alternative approach to control glycolysis.

The wheat powdery mildew resistance gene Pm4 also confers resistance to wheat blast carrying the effector AVR-Rmg8. The authors propose the Pm4f allele as the most effective allele to deploy in Bangladesh and Zambia.

Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but seems to be largely redundant physiologically.