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Tissue stiffness mediated by Piezo1 is shown to regulate the expression of diffusive guidance cues in the developing Xenopus laevis brain, revealing a crosstalk between mechanical signals and long-range chemical signalling.

CRISPR gene targeting in multicellular organisms results in genetic mosaics, limiting knockout efficiency. Here, the authors develop an improved system using Cas12a with multiple guides per gene, and demonstrate high accuracy and superior knockout efficiency in fruit flies.

In this study, the authors present optimization and efficacy testing of apolipoprotein-based lipid nanoparticles for delivering various nucleic acid therapeutics in vivo to immune cells and their progenitors in the bone marrow.

Inherited mitochondrial DNA mutations can result in diverse clinical phenotypes. Here, the authors characterise a heteroplasmic tRNA^Ala mutation (m.5019A>G) in mice and demonstrate that macrophages carrying this mutation display altered function and metabolism in vitro, along with increased type I IFN release following LPS challenge in vivo.

Here the authors show that transient cell cycle arrest reprograms CD8⁺ T cells into a highly energized state, increasing proliferation and antitumor activity and boosting efficacy of immunotherapies in cancer models.

CAR-T cell efficacy is often limited by the inability to maintain a memory T cell program. Here, the authors show that intrinsic CXCR4 expression enhances CAR-T cell persistence and memory differentiation in acute myeloid leukemia.

Kidney organoids derived from human pluripotent stem cells are infused in a normothermic machine perfusion system to condition explanted porcine kidneys, and the feasibility and viability of their in vivo engraftment are demonstrated.

The emergence of SARS-CoV-2 variants resistant to neutralizing antibodies poses a constant threat. Here, the authors identify a camelid antibody targeting ACE2 which broadly inhibits infection and provides antiviral protective effects in vivo after nasal inoculation.

González-Gualda, Reinius et al. demonstrate that platinum-based chemotherapy-induced senescence promotes malignancy in ovarian and lung cancer via TGFβ ligands, with evidence in mouse models validated in clinical samples. Concomitantly blocking TGFβ signaling with chemotherapy reduces tumor burden and increases survival in mice.

A wearable that continuously measures the concentration of a drug is demonstrated in humans.

Neville, Ferguson et al. show that non-canonical Polycomb repressive complex 1.1-mediated gene silencing is antagonized by DOT1L and is required for the therapeutic efficacy of Menin and DOT1L inhibitors in mixed-lineage leukaemia.

One of three back-to-back papers to show dosage of BACH2 can modulate T cell differentiation and function and how we might apply this to enhance chimeric antigen receptor T cell therapies for cancer.

An anti-HIV-1 antibody that targets an N332_gp120 glycan-independent V3 epitope, a site of Env vulnerability, can decline viremia in HIV-1-infected humanized mice while overcoming classical V3 escape mutations.

Oscillatory Min protein patterns prevent abnormal bacterial cell division. Now it is shown that Min pattern formation is resource efficient and involves wavelength-invariant oscillations that are robust to physiological changes.

Antigen presentation in skull bone marrow by hematopoietic stem and progenitor cells induces myelopoiesis and generates CD4⁺ regulatory T cells in a mouse model of ependymoma, promoting immune tolerance. Treatment with anti-GM-CSF antibody has antitumor effects that are augmented by immunotherapy.

Doudna and colleagues discuss recent advances in the targeted delivery of genome editors in vivo, offering a framework for the rational design of delivery systems.

The viscosity of tumour cells is shown to govern their ability to disseminate through the bloodstream and extravasate, establishing a key biomechanical factor of metastasis.

The antitumor efficacy of chimeric antigen receptor natural killer cells is enhanced by genetic engineering.

RNAi therapy has huge potential but effective delivery to target location is a major issue. Here, the authors report on the delivery of RNAi to tumors using self-agglomerating nanohydrogels that can overcome the different delivery barriers and supply multiple RNAi payloads.

Squeezed light field microscopy (SLIM) combines ideas from tomography and compressed sensing with light field microscopy to enable volumetric imaging at kilohertz rates, as demonstrated in blood flow imaging in zebrafish and voltage imaging in leeches and mice.

In a phase 1b/2 trial, an off-the-shelf vaccine using gorilla adenoviral and modified vaccinia Ankara vectors with over 200 mutated peptides known to be present in persons with mismatch-repair-deficient tumors is safe and elicits neoantigen-specific T cells in individuals with Lynch syndrome.

A large-scale mouse study reveals that while existing epigenomic data detect many developmental enhancers, a substantial fraction is missed - highlighting the need for expanded resources to fully annotate enhancers genome-wide.

Here, the authors systematically map metaproteomic responses of ex vivo human gut microbiota to common therapeutics, identifying several drug classes inducing strong disruptions to the microbial ecosystem, providing a comprehensive view of how drugs influence gut microbiome function and ecology at the protein level.

Membrane ion channels can be responsive to a variety of stimuli such as pressure, temperature, or pH. Here, the authors show that simply shining 365 nm light activates a native potassium channel in rodent pain-sensing neurons, delivering powerful analgesia without drugs or genetic manipulations.

De la Rosa et al. developed an in vivo CRISPR screening system to dissect macrophage regulation in multiple sclerosis models, revealing key cytokine signaling pathways that control myeloid cell behavior in neuroinflammation.

Systematic screening of transcription factors reveals conserved mechanisms governing cortical radial glia lineage progression across primates and provides a framework for functional dissection of gene regulatory networks in human cortical neurogenesis.

Prior hypoglycemia alters the paracrine interaction between islet α and δ cells, leading to impaired counter-regulatory glucagon secretion through somatostatin hypersecretion, increasing the risk of recurrent hypoglycemia.

Polyamines prevent the action of kinases on acidic phosphorylatable motifs in spliceosomal proteins, thus providing a mechanism for metabolite-mediated regulation of alternative splicing in cells.

Phylodynamic modelling shows how the changing antibiotic landscape and genetic determinants of resistance shape real-world gonococcal dynamics. Experiments validated that determinants with identical resistance phenotype differed in impact on fitness.

Gallrein et al. pair functional assays with clocks to compare chronological versus biological age of single neuron types in C. elegans, to probe their vulnerability or resilience to neurodegeneration, and use an in silico screen to identify neuroprotective drugs.

Here, the authors use a mouse model of multiple sclerosis to show that CD38⁺Foxp3⁺ T_reg cells persist in postinflammatory CNS tissues and are needed for maintaining immune homeostasis. These localized stress-tolerant T_reg cells have developed mechanisms to exploit the limited availability of IL-2 in this tissue.

Via high-throughput imaging and tracking over 140 million single mycobacteria, the authors show that drug- and strain-specific killing predict treatment outcomes, with potential to improve drug development and personalized therapy.

Bacteria secrete polysaccharides essential for colonization and infections. Here, the authors reveal the structure and mechanism of WzaB, a Class-3 OPX protein, uncovering a distinct trans-envelope secretion complex driving critical polysaccharide export in diderm bacteria.

An amphiphilic mimotope vaccine can be used in tandem with Food and Drug Administration (FDA)-approved CD19 CAR-T cell products.

Mitochondrial damage is a central pathological mechanism of cerebral ischemia-reperfusion injury. This study develops a bioengineered nanolamellar system to sequentially restore neuronal cell mitochondrial function and modulate microglial polarization to mitigate ischemia-reperfusion injury.

Using chemical photoswitchable reagents to exert purely wavelength-dependent control over biological systems in deep tissue and in vivo requires a concentration-independent design paradigm. Here, such photoswitchable ligands are realized by ensuring that E/Z isomers have opposing efficacies yet similarly high affinity, allowing them to probe transient receptor potential C4 and C5 channel functions up to the tissue level.

Current antimalarials often fail to target mature stage V gametocytes. To aid antimalarial drug discovery, the authors present a preclinical malaria transmission-blocking drug research platform, using engineered parasites, that facilitates the screening for gametocytocidal compounds in vitro and the evaluation of transmission-blocking drug activity in vivo.

UCHL5 is a deubiquitinating enzyme that cleaves Lys-48-linked polyubiquitin chains. Here, the authors discover through in-vivo CRISPR-Cas9 screens that Uchl5 is involved in immune evasion and modulation of extracellular matrix deposition in head and neck squamous cell carcinoma.

The Akt-mTOR axis influences cell activation, differentiation and metabolism. Jordan and colleagues show that thymic and inducible T_H17 cells exhibit different requirements for mTORC1 and mTORC2 as well as Akt isoforms.

Heparan sulfate proteoglycans facilitate the assembly of clusters of glycoRNAs and cell surface RNA-binding proteins, which negatively modulate VEGF-A signalling and angiogenesis.

Bessler et al. developed a human organoid model for H3.3K27M-altered diffuse midline glioma that recapitulates key tumor features and demonstrated its utility for modeling CAR T cell and microglia functions.

Moral-Sanz, Fernández-Carrasco and colleagues identify senolytic properties of sea anemone-derived pore-forming toxins, with selectivity mediated by senescence-associated lipid profiles. An optimized senotoxin improves the efficacy of chemotherapy in mouse models.

By performing a CAR-adapted base-editing screen of phosphatidylinositol-3-kinase delta (PI3Kδ, PIK3CD), Bucher et al. identify mutations affecting endogenous PI3K–AKT signaling that enhances CAR T cell antitumor potency.

Dense mapping of DNase I cleavage sites across the whole yeast genome by next-generation sequencing reveals a global view of the binding of regulatory proteins to genomic DNA. The high resolution allows the identification of new binding sites for known factors as well as the de novo derivation of factor binding motifs.

Identifying genes involved in MYC-driven lymphoma reveals therapeutic vulnerabilities. Here, the authors show by using CRISPR knockout screens in primary cells in vivo that the GATOR1 complex suppresses MYC-driven lymphomagenesis, and that GATOR1-deficient lymphomas are sensitive to mTOR inhibitors.

Phosphorylation-dephosphorylation and ubiquitination tune TCR signaling to avoid self-reactivity. Kim and colleagues show that acetylation also modulates TCR signaling.

The genetically encoded sensor hCRAFi-CCR2 enables detection of chemokines binding to the CCR2 receptor, such as the main ligand CCL2 but also CCL7, CCL8, CCL13 and CXCL1. The sensor’s capabilities are demonstrated in cell culture and in various mouse models in vivo.